>>I'M FRANCIS COLLINS. THE DIRECTOR OF THE NATIONAL INSTITUTES OF HEALTH AND DELIGHTED TO WELCOME YOU TO THE 2011 NIH ALZHEIMER'S RESEARCH SUMMIT, PATH TO PRECISION MEDICINE FOR TREATMENT AND PREVENTION. I RECALL NINE YEARS AGO SPEAKING TO THE FIRST OF THESE REMARKABLE ASSEMBLIES OF SOME OF THE BRIGHTEST MINDS IN ALZHEIMER'S RESEARCH AND INNOVATORS IN OTHER DISEASES AS WE SET OUT TO RETHINK THE ENTERPRISE AND TRY TO CREATE AN APPROACH THAT ENCOURAGES THE DISCOVERY, DEVELOPMENT AND DELIVERY OF DISEASE MODIFYING AND SYMPTOMATIC TREATMENTS FOR PATIENTS AT ALL STAGES OF THE DISEASE. THE BLUE PRINTED FOR THAT INTEGRATED TRANSLATIONAL RESEARCH AGENDA PUT FORWARD BY THE FIRST ALZHEIMER'S SUMMIT IN 2021 WAS ENHANCED AT SUBSEQUENT SUMMITS INCLUDING THOSE FOCUSSED ON ALZHEIMER'S DISEASE, ALZHEIMER'S DISEASE AND RELATED DEMENTIAS AND CARE AND SERVICES. SO NOW, ARMED WITH THIS FRAMEWORK AND BOYED WE HAVE INFORMED NEW PARTNERSHIP TO LAY THE FOUNDATION OF PRECISION MEDICINE FOR ALZHEIMER'S. LET'S ALL ADMIT THIS PAST YEAR WAS AN EXCEPTIONALLY CHALLENGING ONE FOR ALL OF US AND FOR THE DEMENTIA COMMUNITY IN PARTICULAR. IT WAS A YEAR OF DISRUPTION AND LOSS BUT AT THE SAME TIME FIGURING OUT HOW TO OVERCOME AND RESILIENCE AND THE TRIUMPH OF SCIENCE MADE IT POSSIBLE FOR US TO BE NOW TO BE AT A PLACE OF VACCINATIONS WITH COMING OUT OF THIS WORSE PANDEMIC IN 100 YEARS. I'D LIKE TO REASSURE YOU WE AT NIH HAVE NOT LOST SIGHT OF THE URGENCY TO CONQUER ALZHEIMER'S AND RELATED DEMENTIAS. SO THIS WEEK FOR FOUR VERY INTENSE DAYS, WE COME TOGETHER VIRTUALLY FOR PROGRESS MADE AND SHARE WAYS TO COME TOGETHER AND WE'LL HEAR ABOUT PROMISING NEW RESEARCH. I CAN MENTION JUST A FEW OF THOSE ITEMS. GENETICS DISCOVERIES, INSIGHTS INTO THE BIOLOGY OF ALZHEIMER'S RISK AND RESILIENCE. THE IMPACT OF SEX DIFFERENCES ON MOLECULAR MECHANISMS OF BRAIN AGING AND DEMENTIA. COMPREHENSION MEDICINE RESEARCH THROUGH THE USE OF EXISTING DATA FROM DEEPLY PHENOTYPED COHORTS AND NEWLY ESTABLISHED BUT DIVERSE COHORTS. THE CONTRIBUTIONS OF THE ACCELERATING MEDICINES PARTNERSHIP AND ITS ALZHEIMER'S PROJECT TO OUR ABILITY TO DISCOVER AND VALIDATE NEW THERAPEUTIC TARGETS IN BIOMARKERS AND IDENTIFY MOLECULAR SUB TYPES OF THE DISEASE. A CRITICAL AREA WE WERE JUST DISCUSSING BEFORE WE WENT LIVE TRYING TO UNDERSTAND WHAT ARE WE LUMPING TOGETHER WHEN WE USE THIS DIAGNOSIS OF ALZHEIMER'S AND TO WHAT EXTENT WILL UNDERSTANDING THOSE SUB TYPES LEAD US TO MORE OF A PRECISION MEDICINE APPROACH TO PREVENTION AND TREATMENT. WE'LL ALSO BE HEARING ABOUT AN ARRAY OF NEW DRUG CANDIDATES IN LATE-STAGE DEVELOPMENT AND NEW AND CLINICAL CANDIDATES AS WELL. THE USE OF ARTIFICIAL INTELLIGENCE AND DEEP LEARNING AND COMBINATION THERAPY DEVELOPMENT. AND THE GROWING TOOL KIT OF BIOMARKERS. SOMETHING WE PUT A LOT OF EFFORT INTO AND NOW EMERGING IN INTERESTING WAYS. SO IT'S GOING TO BE QUITE A FOUR DAYS. PUT ON YOUR SEAT BELTS BUT WE NEED TO THINK ABOUT THIS AS AN OPPORTUNITY TO SURVEY THE FIELD, IDENTIFY AREAS OF POTENTIAL COLLABORATION THAT HAVEN'T YET BEEN FULLY CAPITALIZED. TO FOCUS ALL OF OUR EFFORTS IN MAKING SURE ALL THE DATA'S ACCESSIBLE FOR EVERYONE ON SOMETHING THEY CAN DO TO ADVANCE THE FIELD. OPEN ACCESS HAS TO BE OUR WATCH BECAUSE WE DO AFTER ALL HAVE ONLY FOUR YEARS TO MEET THE GOAL TO TREAT AND PREVENT ALZHEIMER'S AND RELATED DEMENTIAS BY 2025. WE ARE MOVING FORWARD WITH PROMISING ADVANCES BUT THAT'S A VERY AGGRESSIVE AGENDA. I'D LIKE TO APPEAL TO ALL OF YOU, IN THE COURSE OF THE NEXT FOUR DAYS TRY TO THINK OF THIS AS NOT JUST A SERIES OF DISCONNECTED ITEMS AND LOOK FOR SYNERGY AND THINGS TO COME MIND WHEN YOU BRING TOGETHER INNOVATIONS AND SPARKS CAN FLY. THIS IS IN FULL PRECISION MEDICINE MODE WITH ALL THE PROMISE IT HOLDS AND IT WILL BE VERY MUCH EXPLORED THIS WEEK. SO PLEASE, LET'S PRESS ON. AFTER ALL, PEOPLE SUFFERING FROM THIS CONDITION AND THEIR FAMILIES DESERVE NOTHING LESS THAN OUR ABSOLUTE FULL ENGAGEMENT AND I KNOW I CAN COUNT ON ALL OF YOU TO DO THAT THIS WEEK AND GOING FORWARD. THE STAKES ARE VERY HIGH COMING UP WITH ANSWERS IS A DESPERATE NEED. WE'VE MADE GREAT PROGRESS BUT WE STILL HAVE MORE TO DO. SO WITH THAT, AND WITH MY WARM WORDS OF WELCOME TO ALL OF YOU, PLEASE NOW WELCOME DR. RICHARD HODES, DIRECTOR OF THE NATIONAL INSTITUTE ON AGE WHO WILL VERY ABLY LEADS NIH'S EFFORTS AGAINST ALZHEIMER'S AND RELATED DEMENTIAS. >> THANK YOU FOR THAT WONDERFUL COMPREHENSIVE, INSPIRATIONAL, EXHORTATIONAL BEGINNING TO THE MEETING. THE SUMMIT FALLS IN CONTEXT OF THE NATIONAL ALZHEIMER'S ACT SIGNED INTO LAW IN 2011. THE PLAN WAS RELEASED IN 2012 AND HAS AND RETAINS FIVE PRIMARY GOALS AND THE PREVENTION AND EFFECTIVE TREATMENT OF ALZHEIMER'S AND RELATED DEMENTIAS BY 2025 AND THE GOALS INVOLVING ENHANCED CARE AND QUALITY SUPPORT FOR PEOPLE WHO HAVE ALZHEIMER'S ALSO REMAIN VERY MUCH THE SUBJECT OF RESEARCH AND OF SUMMITS WE'VE SEEN ON THE REGULAR THREE-YEAR CYCLE OF SUMMITS. SO I WANT TO SHARE WITH YOU AN INTERESTING ACCOMPANIMENT TO OUR PLANNING PROCESS IS REQUIREMENT BY LAW FOR THE DIRECTOR OF NIH, FRANCIS COLLINS, EVERY YEAR THROUGH 2025 TO SUBMIT TO CONGRESS DIRECT -- THOUGH WITH OPPORTUNITY FOR COMMENT WITHOUT CHANGE BY THE ADMINISTRATION, THE DEPARTMENT AND THE NATIONAL ADVISORY COUNCIL INDICATING WHAT IS NEEDED IN TERMS OF INCREMENTAL RESOURCES EACH YEAR TO REMAIN EFFICIENCY THEED GOALS OF THE PLAN INCLUDING THE ACHIEVEMENT OF EFFECTIVE INTERVENTIONS BY 2025. SO [NO AUDIO] THAT BEGAN IN 2012 AS FRANCIS COLLINS NOTED THROUGH 2020 THAT INCLUDED CARE SUMMITS, SUMMITS ON THE RELATED DEMENTIAS AND THIS SERIES OF SUMMITS ON ALZHEIMER'S DISEASE, 2012, 2015, 2018 AND NOW 2021. AND WE HAVE INPUT FROM ACADEMICS, PRIVATE SECTOR TO DEVELOP A SERIES OF COMPREHENSIVE RESEARCH MILESTONES PUBLISHED FROM A POINT OF PLACE WHERE YOU CAN SEE THEM ALL AND MILESTONES COUPLED WITH CRITERIA FOR MEETING AND ACHIEVING THEM BECOME THE PART OF PROFESSIONAL ESTIMATE THAT IS SUBMITTED TO CONGRESS EACH YEAR. I MUST SAY IT'S HAD AN ENORMOUS IMPACT ON CONGRESS, THE WORK ALL OF YOU HAVE DONE, THE FORMULATION OF A PLAN AS IMPRESSED UPON CONGRESS, BOTH PARTIES, BOTH HOUSES, THE SERIOUSNESS AND FEASIBILITY AND SCIENCE BEHIND THE REQUEST FOR ADDITIONAL FUNDS HAVE BEEN ENORMOUSLY IMPORTANT IN ACHIEVING THE GOALS AND RESOURCES IN ORDER TO ATTACH THOSE GOALS. SO THE BUDGET TO POINT OUT IS ACCOMPANIED BY A NARRATIVE EACH YEAR THAT IS A PROGRESS REPORT ILLUSTRATING THE PROGRESS OVER THE PRIOR YEARS. THE LINK HERE I'D ENCOURAGE YOU TO LOOK AND YOU HAVE CONTRIBUTED AND WILL CONTRIBUTE DURING THE COURSE OF THIS SUMMIT. THIS IS A CHRONOLOGY OF THE APPROPRIATIONS THAT CAME TO THE NATIONAL INSTITUTE ON AGING TARGETED FOR ALZHEIMER'S AND DEMENTIA RELATED DISEASE AND TO THE PRESENT FISCAL YEAR, 2021, EACH YEAR THE INCREASE FROM 300 TO $425 MILLION EACH YEAR. SHOWN IN THE SLOPE HERE OF APPROPRIATIONS INCLUDING THIS QUITE DRAMATIC INCREASE FROM 2014 TO 2021 THE UPPER BAR AND THE BOTTOM ADJUSTED FOR INFLATION. IT'S QUITE REMARKABLE AND REALLY UNPRECEDENTED INCREASE AND WHERE HE FLECTS THE WORK -- REFLECTS TO THE WORK YOU'VE PUT AND THE FORMULATION OF OUR BYPASS BUDGET WHICH SHOWS NOT JUST IN ABSTRACT DOLLAR FIGURES BUT IN REAL AND ACHIEVABLE MILESTONES AND GOALS AND THE WAY IN WHICH WE CAN APPROACH THIS FIGHT AGAINST ALZHEIMER'S AND ACHIEVE THE STATED GOALS IMPRESSED POLICY MAKERS REFLECTED IN OUR APPROPRIATIONS. IT'S REFLECTED WITH THE ENTHUSIASM AND EXCITEMENT WE ALL FEEL AS MEMBERS OF THE RESEARCH COMMUNITY. SO AGAIN, YOU CAN SEE FROM THE BOTTOM THE RECOMMENDATIONS FROM ALL THE SUMMITS OVER THE NEXT FEW DAYS LEADING TO THE IMPLEMENTATION RESEARCH MILESTONES AND IN TURN TO FUNDING OPPORTUNITIES BY PARTNERSHIPS ALL OF WHICH DRIVE THE RESEARCH ENGINE. SO HERE IN TERMS OF THE MILESTONES AND ACCESSIBLE TO ALL OF YOU, THE LINK AT THE BOTTOM WE NOW HAVE 150 MILESTONES AND TARGETED STRATEGIES FOR REACHING THEM INFORMED BY THE INPUT OF ALL OF YOU IN THE PAST AND NOW WILL BE BY THE CURRENT SUMMIT AND PARTICIPATION IN ADDRESSING THE RESEARCH STRATEGIC PLANS. TRACKING THE RESEARCH AND NATIONAL ALZHEIMER'S DISEASE AND RESEARCH PORTFOLIO WHICH LISTED ACTIVE RESEARCH PROJECTS FROM NOW GREATER THAN 40 FUNDING AGENCIES IN THE U.S. AND ABROAD ORGANIZED IN AN ONTOLOGY PUT TOGETHER BY THE ALZHEIMER'S ASSOCIATION TOGETHER WITH NIA SO AS A GLOBAL COMMUNITY WE CAN RECOGNIZE ALL THAT'S GOING ON, LOOK FOR GAPS, LOOK FOR OPPORTUNITIES TO COLLABORATE AND STRESSING THE IMPORTANCE OF TAKING A LOOK IN REAL TIME AS WE UPDATE THIS EACH YEAR. SO HERE SHOWN AROUND PUBLIC PRIVATE PARTNERSHIPS EMPHASIZE THE DIVERSITY OF NIA AND NIH SUPPORTED ALZHEIMER'S RESEARCH AND ON THE NEXT SLIDE THE MOST EXCITING AREAS RIPE FOR OPPORTUNITIES RIPE FOR TOPIC AT THE CURRENT RETREAT. THIS IS AN ILLUSTRATION OF THE NUMBER OF NEW PROJECTS EACH YEAR FROM 2008 TO 2019. THE LAST YEAR FOR WHICH WE HAVE THE COMPLETE INFORMATION BY RESEARCH CATEGORIES. YOU CAN SEE RESEARCH RESOURCES, DEMENTIA CARE AND STUDIES, TRANSLATIONAL RESEARCH AND CLINICAL INTERVENTIONS, DIAGNOSIS AND MOLECULAR GENESIS AND YOU SEE THE GOALS WITH EVER INCREASING INTENSITY. AS WE LOOK AT THE WORKFORCE, AS YOU COME TO BEAR AND PUT YOUR INGENUITY AND CREATIVITY AND HARD WORK IN THE FIELD, IT'S NOTABLE SINCE 2015 THROUGH 2020, ABOUT A THIRD OF THE AWARDEES FROM NIA'S PROGRAMS AND ALZHEIMER'S RELATED DEMENTIAS WERE NEW OR EARLY STAGE INVESTIGATORS NOT HAVING PRIOR NIH SUPPORTED GRANTS. EQUALLY IMPRESSIVE, ABOUT A FOURTH OF THE AWARDS HAVE GONE TO PEOPLE NEW IN THE FIELD DEFINED AS THOSE AS HAVE NEVER APPLIED FOR RESEARCH IN THIS FIELD BEFORE. SO ALL THE ESTABLISHED INVESTIGATORS IN THE FIELD JOIN EACH YEAR BY COHORTS OF NEW INVESTIGATORS FOREVER BUILDING THE MOMENTUM IN PURSUIT OF OUR GOALS. WE HEARD PRECISION MEDICINE MENTIONED IN THE INTRODUCTION BY FRANCIS COLLINS AND HERE IN THE TITLE AND CHARGE OF OUR SUMMIT. THE GOAL IS TO GO FROM WHICH THE PATIENT POPULATION IS TREATED ONE BY ONE AND TREATING DIVERSE POPULATIONS AND THE MAXIMAL APPROACH MAY BE DIFFERENT AND THE GOAL IS TO FIND OUT SUB POPULATIONS OF DISEASE CHARACTERIZED BY DIFFERENT PATHWAYS OR COMBINATIONS OF PATHWAYS THAT ARE MOST IMPORTANT IN GIVEN INDIVIDUALS AND TO TARGET TREATMENTS OR COMBINATIONS OF TREATMENTS TO THESE. SO HERE'S THE CONTINUUM FROM EARLIEST IDENTIFICATION OF POTENTIAL TARGETS THROUGH DEVELOPMENT AND VALIDATION TO THE VALLEY OF DEATH OF TRANSLATION FINALLY TO CLINICAL TRIALS. I WANT TO STRESS NEXT THE EFFORTS MADE TO BRIDGE THE VALE OF DEATH IN THE PIPELINE -- VALLEY OF DEATH IN THE PIPELINE OF DRUG DISCOVERY AND NERVOUS SYSTEMS DISORDER AND THE A.D. DEVELOPMENT AND PROGRAM AND THE BLUEPRINT OF THERAPEUTICS. THIS IS A LIST, HARD TO READ IN DETAIL IN THIS SLIDE BUT SHOW THE 11 PRE CLINICAL DEVELOPMENT PROGRAMS THAT MOVED TO PHASE ONE AND PHASE TWO AND AWARDEES AND ACADEMIA AND SMALL MOLECULES AND THEIR THERAPIES. AGAIN, AN INCREASING DIVERSITY AS THESE ME OF FORWARD IN THE MAINSTREAM OF CLINICAL TRIALS MORE ADVANCED CLINICAL TRIALS AND WE ADDRESS THE APPROACH USING EACH OF THESE DIVERSE TARGETS IN THE RIGHT POPULATION AT THE RIGHT TIME. TO TREAT WHAT IS NOTED HERE NOW PART NOW IN TERMS OF INFRASTRUCTURE AVAILABLE TO FACILITATE AND BYPASS THE ROAD BLOCKS TO BE CONSULTED BY PEOPLE ENGAGED IN DRUG DEVELOPMENT TO LOOK AT VARIOUS COMPONENTS OF NEEDS AND ADDRESS THEM IN AN INDIVIDUAL WAY AND A BALANCE OF RESEARCH TO OPTIMIZE. LOOKING AT THE COMPONENTS OF DISCOVERY GOING BACK TO THE ALZHEIMER'S DISEASE SEQUENCING PROJECT BY THE BEGINNING OF THIS YEAR WE'RE SEEING 17,000 GENOMES OVER POPULATIONS ILLUSTRATED HERE. BY THE END MUCH THIS YEAR, THE WINTER OF '21, '22 EXPECTED TO HAVE SOME 30,000 GENOMES. IMPORTANTLY, WE'LL LOOK AT COMBINATIONS OF PHENOTYPES TO ALLOW POOLING AND ANALYSIS AND FUNCTIONAL GENOMICS TO UNDERSTAND THE GENETIC VARIANCY AND THE APPLICATION OF ARTIFICIAL INTELLIGENCE AND IDENTIFYING THE MEANING AND TRANSLATIONAL SIGNIFICANCE OF THE DISCOVERIES. THE AMP AD PROJECT THAT BEGAN IN 2014 WAS GROUNDBREAKING AND HAD SUCCESS AND BRINGING TOGETHER OF SEVEN LARGE SCALE TEAMS ACROSS DISCIPLINES AROUND INSTITUTIONS AND FAIR TO SAY THE ESTABLISHMENT OF REMARKABLE AND CUTTING EDGE SOCIOLOGY OF COLLABORATION AND SHARING OF INFORMATION WITH THE COMMON DATABASE AVAILABLE TO ALL AND 542 UNIQUE TARGETS NOMINATED AND MADE AVAILABLE WITH SUPPORTING EVIDENCE THROUGH THE ALL AVAILABLE STAGE AS WE MOVE FROM AMP AD1.0 HERE TO AMP AD 2.0 AND WANT TO NOTE AGAIN THE PARTNERSHIPS IN THE BOTTOM LEVEL, ALONG WITH PRIVATE FOUNDATIONS AND COMPANIES THAT HAVE COME TO JOIN THE EFFORT. THIS AMP AD 2.0 BRINGS TOGETHER EIGHT RESEARCH TEAMS AND 20 DIFFERENT ACADEMIC AND NINE PUBLIC PRIVATE PARTNERS AND EXPAND OMICS TO LOOK AT MORE DIVERSE POPULATIONS, GENERATE LONGITUDINAL STUDY PROFILING ACROSS THE POPULATIONS AND EXPAND THE SINGLE CELL PROFILE FOR IDENTIFICATION OF THEIR TARGETS AND THEIR ENGAGEMENT. THE AD KNOWLEDGE PORTAL, YOU CAN SEE WILL BE INTEGRATING AMP AD DATA ALONG WITH THAT FROM MOVE AD AND A SIMILAR EFFORT AROUND VASCULAR AND METABOLIC FACTORS IN AD, RESILIENCE AD AND LOOKING AT THE FACTORS WHICH PROTECT AGAINST THE DEVELOPMENT OF CLINICAL DEMENTIA EVEN WHEN RISK FACTORS EXIST AND THE MOLECULAR MECHANISMS OF NEUROPSYCHIATRIC SYMPTOMS INTEGRATED IN A PORTAL INVOLVED IN THE RESEARCH COMMUNICATION AN OPEN SCIENCE TO THE GLOBAL COMMUNITY. OPEN SCIENCE AGAIN IN TERMS OF TREAT AD MENTIONED IN THE ENABLING TOOLS FOR STUDYING DISEASE AND BIOLOGY THROUGH SUCH THINGS AS DRUG DISCOVERY AND AI, MODEL AD AND TAKING POTENTIAL TARGETS THROUGH PRE CLINICAL STAGES ALREADY DEVELOPED MOUSE MODELS CODING AND NON-CODING. I WANT TO EMPHASIZE ALL THESE INCLUDING THE MOUSE MODELS THEMSELVES ARE FREELY AVAILABLE TO THE RESEARCH COMMUNITY AS ARE THE NEW MODELS ABOUT TO BE STUDIES. WE CONTINUE TO ENGAGE IN THESE EFFORTS. THE HETEROGENEITY AND DIVERSITY OF COHORTS IN SPECIAL POPULATION LESSONS WE LEARNED ACROSS THE FIELD OF HEALTH AND MEDICINE EMPHASIZED WITH OUR EXPERIENCES THROUGH COVID AND IT'S IMPACT ON DIFFERENTIAL POPULATIONS SHOWN HERE WE'LL BE LOOKING AT EXPANDING POPULATIONS OF AFRICAN AMERICAN, MEXICAN AMERICAN AND OTHER HISPANIC POPULATIONS LOOKING AT THOSE THAT ARE DIVERSE IN TERMS OF AMYLOID STATUS AND OTHER MUTATIONAL PROFILES. DOWN'S SYNDROME AS THE LARGEST POPULATION OF DIFFERENTIALLY VULNERABLE POPULATIONS, ALL THESE ADDING TO THE GENETICS AND PHENOTYPES AND OUR APPRECIATION OF EVER INCREASING DIVERSITY TO DRIVE THE PERSONALIZED TARGETED TRANSLATIONAL AND ULTIMATELY INTERVENTIONS. THE ALZHEIMER'S RESEARCH CENTER HAS AN IMPORTANT PART OF OUR EFFORTS. YOU CAN SEE WHAT ALLOWED US TO ENGAGE INSTITUTIONS AND FURTHER DIVERSITY OF GEOGRAPHIES AND POPULATIONS TO BUILD TO THE POINT WHERE THEY ARE ARE CONTRIBUTING IN THE ALZHEIMER'S DISEASE RESEARCH CENTER NETWORK HERE FINALLY TO EMPHASIZE THE HIGH PRIORITY BASIC RESEARCH AREAS AROUND THE CLOCK CONVERGING TO THE CENTER ON TRANSLATION AND THE ULTIMATE GOAL OF DIAGNOSTIC AND THERAPEUTIC AND PREVENTIVE INTERVENTIONS. I THANK ALL FOR BEING A PART OF WHAT WILL BE AN EXCITING NEXT FOUR DAYS AND HAPPY TO TURN THE INTRODUCTION OF THE MEETING TO OUR COLLEAGUE AND ABLE DIRECTOR, ELIEZER MASLIAH. >> THANK YOU, RICHARD, FOR YOUR REMARKS AND INTRODUCTION AND FOR ALL THE AMAZING LEADERSHIP LEADING TO THE 2025 GOAL AND ALL YOUR SUPPORT FOR PUTTING TOGETHER THESE EXCITING MEETING -- THIS EXCITING MEETING. SO WE HAVE A VERY EXCITING MEETING FOR YOU TODAY. WE WILL START WITH TWO PLENARY SESSIONS AND THESE WILL BE FOLLOWED BY A TOTAL OF SEVEN SESSIONS OVER FOUR DAYS. THE FIRST SESSION WILL BE TODAY, THIS MORNING ON DE CONSTRUCTING DISEASE COMPLEXITY. FOLLOWED BY TOMORROW'S SESSION ON ENABLES INFRASTRUCTURE AND INCENTIVES TO IMPROVE REPRODUCIBILITY AND TRANSLATABILITY OF SCIENCE AND THEN WE'LL HAVE A SESSION ON ACCELERATING THERAPY DEVELOPMENT AND THEN ON THE WEDNESDAY WE'LL HAVE A SESSION ON DIVERSIFYING THE THERAPEUTIC TIME LINE OR PRECISION MEDICINE THE FOCUS OF OUR SUMMIT THIS YEAR FOLLOWED BY EMERGING BIOMARKERS WHICH IS A VERY IMPORTANT COMPONENT TOWARD THE GOAL OF PRECISION MEDICINE AND FINALLY DAY FOUR, ON THURSDAY, WE'LL HAVE A SESSION ON ADVANCING DRUG REPURPOSING AND COMBINATIONAL THERAPY WHICH IS AN IMPORTANT COMPONENT OF PRECISION MEDICINE APPROACHES AND WE'LL CLOSE WITH UNDERSTANDING THE IMPACT OF EXPOSOME ON BRAIN HEALTH AND ADVANCING ADRD. AT THE END OF EACH OF THESE SESSIONS, WE WILL ALSO HAVE A DISCUSSION THAT WILL BE LED BY THE CO-CHAIRS AND YOU'LL ALSO BE ABLE TO SUBMIT YOUR COMMENTS OR QUESTIONS. THE INSTRUCTIONS FOR THAT WILL BE PROVIDED BY THE CO-CHAIRS. WE'LL ALSO HAVE AFTER SESSION 2, 3 AND 4, PANELS OF OPEN DISCUSSION. IT WILL BE LIVE PANELS OF OPEN DISCUSSION INCLUDING FUNDING INCENTIVES TO PROMOTE COLLABORATIVE RESEARCH AND ANOTHER ON OPEN SCIENCE AND OPEN DRUG DEVELOPMENT AND FINALLY DIVERSIFYING TRANSLATIONAL WORKFORCE AND RECRUITMENT IS A CRITICAL AREA WHERE WE'VE BEEN WORKING HARD IN THE FIELD. OF COURSE TO PUT THIS TOGETHER THERE'S TREMENDOUS EFFORT ACROSS MANY MANY GROUPS BOTH AT NIH AND ALSO WITH MANY OTHER INSTITUTIONS AND I WOULD LIKE TO TAKE THIS OPPORTUNITY TO THANK IN PARTICULAR THE MEMBERS OF THE NIA DIVISION OF NEUROSCIENCE. [LISTING NAMES] AND THEY HAVE DONE EXTRAORDINARY WORK IN PUTTING TOGETHER AN EXCITING MEETING FOR WHICH WE'RE THANKFUL YOUR JOINING US AND FROM THE DIVISION OF SCIENCE. [LISTING NAMES] AND ALSO THIS HAS BEEN A COLLABORATION WITH OUR SISTER DIVISION AT NIA WITH OTHERS AND THIS IS PART OF OUR COLLABORATION WITH NINDS AND THE OFFICE OF DR. COLLINS AND FINALLY ALSO A LOT OF WORK HAS GONE THROUGH THE OFFICE OF COMMUNICATIONS WITH THE OFFICE OF COMMUNICATIONS AND PUBLIC LIAISON AND THE OFFICE OF LEGISLATION POLICY AND INTERNATIONAL ACTIVITY AND ALL THE WORK YOU SEE LOGISTICS, PRODUCTION AND VIDEOCAST FROM OUR COLLEAGUES FROM EDJ, BAV AND THE NIH VIDEOCAST TEAM. AND I ALSO WANT TO ACKNOWLEDGE AND THANK OUR CO-CHAIRS FOR THIS MEETING, DR. LISA BARNES AND ALAN LEVY WHO HAVE DONE WORK COLLABORATING WITH OUR TEAM PUTTING TOGETHER THIS VERY EXCITING PROGRAM AND TO ALL THE SESSION CO-CHAIRS FROM WHICH YOU'LL BE HEARING TODAY HAVE DONE EXTRAORDINARY WORK FEATURING THE ADVANCES ON THE FIELD. IT'S BEEN THREE YEARS SINCE OUR LAST SUMMIT AND YOU'LL SEE THE CONVENIENCES HAVE BEEN ABSOLUTELY EXTRAORDINARY AND WE'RE REALLY DELIGHTED TO SHARE WITH YOU YOUR COMMENTS AND FEEDBACK AND AS DR. HODES MENTIONED THIS IS TAKEN INTO ACCOUNT THE FOLLOWING SESSIONS WHERE WE'LL TAKE INTO CONSIDERATION ALL THE FEEDBACK TOWARDS DEVELOPING THE NEXT PHASES OF THE NATIONAL PLAN. SO I WOULD LIKE NOW TO INTRODUCE OUR PLENARY SESSION SPEAKERS. I'M DELIGHTED TO INTRODUCE DR. LISA BARNES FROM RUSH UNIVERSITY TALKING TO US ABOUT UNDERSTANDING THE IMPACT OF MALE DISPARITIES. A VERY IMPORTANT TOPIC TO ENABLE PRECISION MEDICINE FOR DEMENTIA AND OUR OTHER PLENARY SESSION SPEAKER WILL BE DR. NATHAN PRICE WHO WILL BE TALKING TO US ABOUT MECHANISTIC INSIGHTS AND TECHNOLOGY FOR PRECISION MEDICINE RESEARCH ON AGING AND ALZHEIMER'S DISEASE. SO ONCE MORE, WELCOME, EVERYBODY, TO THE MEETING. EXCITING TO BE WITH YOU AND THANK YOU. GOOD MORNING. I'D LIKE TO THANK THE NIA AND ORGANIZERS OF THE 2021 ALZHEIMER'S RESEARCH SUMMIT. IT IS AN HONOR TO PRESENT ONE OF THE OPENING PLENARIES ENTITLED "UNDERSTANDING THE IMPACT OF HEALTH DISPARITIES TO ENABLE PRECISION MEDICINE FOR DEMENTIA".SO, WE'RE GOING TO GO ON A ROAD TRIP, AND I WANT TO DO THREE THINGS. FIRST, I'D LIKE TO HIGHLIGHT WHAT WE KNOW ABOUT DISPARITIES IN DEMENTIA ACROSS A RANGE OF OUTCOMES. SECOND, I'D LIKE TO DESCRIBE ONE APPROACH THAT WE'RE TAKING AT THE RUSH ALZHEIMER'S DISEASE CENTER, TO UNDERSTAND HETEROGENEITY BETWEEN POPULATIONS, THAT IS WHAT WE TYPICALLY THINK ABOUT WHEN WE DOCUMENT HEALTH DISPARITIES, DIFFERENCES BETWEEN GROUPS. THIRD, I'D LIKE TO MAKE A CASE FOR WHAT I THINK IS NEEDED ON THIS PATH TO PRECISION MEDICINE, AND THAT IS UNDERSTANDING WHY THERE ARE DISPARITIES. IN OTHER WORDS, CENTERING DIVERSITY TO UNDERSTAND THE HETEROGENEITY WITHIN POPULATIONS AND IN DOING SO, I'LL PRESENT DATA THAT TAKES INTO ACCOUNT THE LIVED EXPERIENCE OF OLDER BLACKS IN OUR COUNTRY. ALSO, SOME OF THE DATA THAT I'LL SHOW WILL HIGHLIGHT THE IMPORTANCE OF THE LIVED EXPERIENCE ACROSS THE ENTIRE LIFE COURSE.BUT LET'S START OFF FIRST BY FRAMING THE FOUNDATION FOR PRECISION MEDICINE. PRECISION MEDICINE REPRESENTS AN APPROACH OF PREVENTION AND TREATMENT STRATEGIES THAT TAKE THE INDIVIDUAL VARIABILITY INTO ACCOUNT. TRADITIONALLY IT INCLUDES RESEARCH INVESTIGATIONS THAT WILL ENABLE BETTER ASSESSMENT OF DISEASE RISK, UNDERSTANDING DISEASE MECHANISMS, AND INCREASINGLY IN THE DEMENTIA FIELD, THE USE OF BIOMARKERS FOR DRUG DISCOVERY AND PREDICTION OF OPTIMAL THERAPIES.INCLUSION OF MINORITIZED COMMUNITIES THOUGH IS WHAT WE'RE THINKING ABOUT HERE, RIGHT? SO, PRECISION MEDICINE HAS TO ALSO FOCUS ON THE SOCIAL DETERMINANTS OF HEALTH, THOSE CONDITIONS IN THE ENVIRONMENT IN WHICH PEOPLE ARE BORN, WORK, PLAY, AND AGE: THE SOCIAL DETERMINANTS THAT WE KNOW HAVE A PROFOUND IMPACT ON HEALTH AND HAVE BEEN STUDIED BY PUBLIC HEALTH SCHOLARS FOR CENTURIES. TYPICALLY, PRECISION MEDICINE IS FOCUSED ON THE INDIVIDUAL, BUT AS DR. KHOURY AND COLLEAGUES HAVE STATED, IF PRECISION MEDICINE IS ABOUT THE INDIVIDUAL, PRECISION PUBLIC HEALTH CAN BE SIMPLY VIEWED AS PROVIDING THE RIGHT INTERVENTION TO THE RIGHT POPULATION AT THE RIGHT TIME.THE NIA HEALTH DISPARITIES FRAMEWORK IS A GREAT EXAMPLE OF TAKING SOCIAL DETERMINANTS OF HEALTH INTO ACCOUNT WITH PRECISION MEDICINE. THIS FRAMEWORK ALLOWS US TO BETTER DELINEATE CAUSAL PATHWAYS AND BROADEN THE SCOPE FOR TANGIBLE TARGETS FOR INTERVENTION. IT ALSO REMINDS US THAT WE HAVE TO CONSIDER INTERSECTING DOMAINS AND LEVELS OF INFLUENCE IN EVALUATING HOW THOSE FUNDAMENTAL FACTORS SUCH AS GENDER, AGE, RACE, DISABILITY STATUS, AND IDENTITY; HOW THOSE FACTORS INFLUENCE AGING AND DEMENTIA RISK AND HOW THEY OPERATE ACROSS THE ENTIRE LIFE COURSE.SO, THIS IS AN EXAMPLE OF WHAT WE'RE TRYING TO UNDERSTAND WHEN IT COMES TO PRECISION MEDICINE AND DISPARITIES, THIS CONCEPT OF UNDERSTANDING DIFFERENCES BETWEEN RACES AND ETHNICITIES. THIS IS WORK FROM MAYEDA AND COLLEAGUES FROM 2016, USING DATA FROM OVER 270,000 ENROLLEES IN THE KAISER INTEGRATED HEALTH SYSTEM. I KNOW WE'RE ALL FAMILIAR WITH THESE DATA, IT SHOWS THAT AFRICAN AMERICANS ARE MORE LIKELY TO DEVELOP DEMENTIA, FOLLOWED CLOSELY BY AMERICAN INDIANS AND ALASKAN NATIVES. INTERESTINGLY, ASIAN AMERICANS HAVE THE LOWEST INCIDENCE OF ALL THE GROUPS, A FINDING THAT POTENTIALLY OPENS A PATH FOR US TO INTERROGATE POTENTIAL RESILIENCE FACTORS THAT MIGHT BE IMPORTANT AND LEAD TO LOWER RISK IN THIS POPULATION.IN MORE RECENT DATA FROM THE NORTHERN MANHATTAN STUDY, WRIGHT AND COLLEAGUES DEMONSTRATE SIMILAR PATTERNS OF GREATER BURDEN OF MCI AND DEMENTIA IN DIVERSE PARTICIPANTS. IN A CROSS-SECTIONAL ANALYSIS OF THEIR DATA, THEY REPORTED THAT BLACK PARTICIPANTS WERE TWICE AS LIKELY, AND CARIBBEAN HISPANICS WERE MORE THAN FOUR TIMES AS LIKELY, AS NON-HISPANIC WHITES TO HAVE MCI OR DEMENTIA. NOW THE CAUSES OF THESE DISPARITIES ARE UNKNOWN, BUT AT THE RUSH ALZHEIMER DISEASE CENTER WE HAVE A NUMBER OF HARMONIZED COHORT STUDIES THAT WILL ALLOW US TO GENERATE DATA TO IDENTIFY DISEASE MECHANISMS THAT MAY UNDERLIE MANY OF THESE DISPARITIES.LEVERAGING THE RICH INFRASTRUCTURE OF TWO COHORT STUDIES THAT WE HAVE AT RUSH, THE RELIGIOUS ORDERS STUDY AND THE RUSH MEMORY AND AGING PROJECT KNOWN AS ROSMAP, WE ARE TRYING TO GENERATE DATA ACROSS THESE DIVERSE POPULATIONS. SO, ROSMAP CONSISTS OF OVER 3,700 OLDER PERSONS WHO ENROLL WITHOUT KNOWN DEMENTIA FROM ACROSS THE U.S., THEY ALL AGREE TO ANNUAL DETAILED CLINICAL EVALUATIONS FOR COMMON CHRONIC CONDITIONS OF AGING WITH DETAILED EVALUATION OF RISK FACTORS AND BLOOD DONATION. ALSO, THEY ALL AGREE TO ORGAN DONATION AT DEATH, AND SO WE HAVE OVER 1,700 AUTOPSIES TO DATE. THE SLIDE ON THE BOTTOM RIGHT SHOWS YOU THE STUDY DESIGN, WHERE WE ENROLL PEOPLE WITHOUT DISEASE, WE DOCUMENT THE RISK FACTORS AT BASELINE, AND WE FOLLOW PEOPLE ANNUALLY WITH A ROBUST, COMPREHENSIVE MEASURE -- OR BATTERY OF COGNITIVE FUNCTION TESTS SO THAT WE CAN RELATE THE RISK FACTORS AT BASELINE TO CHANGE IN COGNITIVE FUNCTION OVER TIME TO INCIDENT DISEASE. AND, IN THOSE WHO COME AUTOPSY, WE CAN RELATE THE BASELINE RISK FACTORS TO A RANGE OF PATHOLOGY FROM NO PATHOLOGY TO MORE PATHOLOGY.BUILDING OFF OF THIS UNIQUE RESOURCE, WE HAVE THREE ADDITIONAL COHORT STUDIES THAT FOCUS ON DIVERSITY. THE MINORITY AGING RESEARCH STUDY, THE AFRICAN AMERICAN CLINICAL CORE, AND THE LATINO CORE. THESE THREE COHORT STUDIES TOGETHER CONSIST OF OVER 1,400 OLDER BLACKS AND LATINOS WHO ALSO ENROLL WITHOUT DEMENTIA, AND LIKE ROSMAP THEY'VE ALL AGREED TO ANNUAL DETAILED CLINICAL EVALUATION, WITH RISK FACTOR ASSESSMENTS AND BLOOD DONATION. BUT UNLIKE ROSMAP, ORGAN DONATION IN THESE THREE STUDIES IS OPTIONAL. IT'S NOT REQUIRED, BUT IT'S STRONGLY SOUGHT AFTER WITH EXTENSIVE EDUCATION AND BUILDING OF TRUST WITH THESE COMMUNITIES, EFFORTS THAT HAVE LED TO MORE THAN 150 AUTOPSIES TO DATE. IMPORTANTLY, THERE IS SIGNIFICANT OVERLAP IN RISK FACTORS WITH ROSMAP, AND ALL FIVE COHORTS USE A HARMONIZED COGNITIVE BATTERY THAT ALLOWS US TO MERGE THE DATA, DOCUMENT DISPARITIES, AND IDENTIFY WHAT IS COMMON ACROSS POPULATIONS SO THAT WE MAY INTERVENE ON THOSE COMMON FACTORS.THIS SLIDE SHOWS YOU THE DEMOGRAPHICS CHARACTERISTICS ACROSS RACE AND ETHNICITY FOR OUR FIVE COHORTS. AS YOU CAN SEE, AGE AT BASELINE IS EARLY TO LATE SEVENTIES. THE COHORTS ARE MAINLY FEMALE AND RELATIVELY WELL EDUCATED, ALTHOUGH THERE ARE DIFFERENCES WITH WHITES TENDING TO HAVE SLIGHTLY MORE EDUCATION THAN BLACKS AND LATINOS. TOGETHER, PARTICIPANTS FROM THESE FIVE COHORT STUDIES ARE DEEPLY CHARACTERIZED FOR A RANGE OF PHENOTYPES. THIS SLIDE SHOWS YOU THE LAYERS OF DATA THAT ARE BEING GENERATED FROM THE CLINICAL ALL THE WAY TO THE MOLECULAR LEVEL. AND WITH THE HARMONIZATION ACROSS ALL OF OUR STUDIES, WE ARE WELL POISED TO DO MOLECULAR MULTI-MODAL INVESTIGATIONS ACROSS RACE AND ETHNICITY, INVESTIGATIONS THAT WE THINK WILL PROVIDE NEW DATA AND CLUES TO UNDERSTANDING SOME OF THESE DISPARITIES.THIS SLIDE HERE REPRESENTS DECADES OF WORK, PRIMARILY IN ROSMAP IN OUR STUDIES OF MAINLY OLDER WHITES. BUT BECAUSE OF HARMONIZATION, WE WILL BE ABLE TO GENERATE NEW KNOWLEDGE ON RACIAL AND ETHNIC DIFFERENCES IN THE EXPOSOME; THE TOTALITY OF GENES, PROTEINS, EXPERIENTIALS, PSYCHOLOGICAL AND MEDICAL RISK FACTORS THAT PLAY A ROLE IN DEMENTIA RISK. FURTHER, AS WE CONTINUE TO ACCUMULATE BRAINS FROM OUR DIVERSE PARTICIPANTS, WE WILL HAVE THE OPPORTUNITY TO ACCELERATE TRANSLATIONAL RESEARCH ACROSS RACE AND ETHNICITY, INCLUDING STUDIES THAT DEMONSTRATE HOW CONTEXTUAL FACTORS LINKED TO RACE AND ETHNICITY ASSOCIATE WITH NEURAL PATHOLOGY. WHICH I'LL SHOW YOU A LITTLE LATER IN THE TALK.SO -- AND THESE COHORTS, WE'VE BEEN FOLLOWING PEOPLE WITH ANNUAL EVALUATIONS FOR MANY YEARS, AND WHAT I'M SHOWING YOU HERE IN THE TOP TWO PANELS ARE RATES OF CHANGE FOR DIFFERENT COGNITIVE DOMAINS PLOTTED AS A FUNCTION OF AGE. THE DIFFERENT COLORED LINES REPRESENT THE THREE POPULATIONS, THE BLACKS, WHITES, AND LATINOS. AND YOU CAN SEE AN INCREDIBLE AMOUNT OF HETEROGENEITY IN WHERE PEOPLE START AND HOW FAST THEY DECLINE, BOTH ACROSS AND WITHIN RACE AND ETHNICITY. HOWEVER, IF WE WERE TO RUN A MIXED EFFECTS MODEL ON THESE DATA, WE WOULD GET A PATTERN SHOWN IN THE BOTTOM TWO GRAPHS. IN THE CASE OF BLACKS AND WHITES ON THE LEFT, WE SEE LEVEL DIFFERENCES, WITH WHITES PERFORMING AT A HIGHER LEVEL BUT NO DIFFERENCE IN RATES OF CHANGE OVER TIME. THE PLOT ON THE BOTTOM RIGHT SHOWS PREDICTED PATHS OF CHANGE FROM A MIXED-EFFECTS MODEL FOR LATINOS VS WHITES. HERE WE SEE NO DIFFERENCES IN STARTING LEVEL OR RATE OF CHANGE.SO, ONE OF THE THINGS WE CAN DO WITH THIS DESIGN IS EXAMINE HOW RISK FACTORS RELATE TO COGNITIVE DECLINE. WHEN WE TALK ABOUT PRECISION MEDICINE FOR DEMENTIA, GENETICS IS AN IMPORTANT RISK FACTOR. WE KNOW THAT THE STRONGEST GENETIC RISK FACTOR FOR ALZHEIMER'S IS APOE, BUT IT DOESN'T OPERATE THE SAME ACROSS RACE. MANY STUDIES HAVE SHOWN THAT THE E4 ALLELE HAS A WEAKER EFFECT ON COGNITIVE DECLINE IN BLACKS. E4 HAS A SELECTIVE EFFECT ON EPISODIC MEMORY, WE KNOW THIS FROM MANY, MANY STUDIES. SO, IN OUR STUDY, WE HYPOTHESIZED THAT THE EFFECT OF E4 MIGHT BE WEAKER IN BLACKS BECAUSE MOST STUDIES HAVE USED EITHER BRIEF SCREENING MEASURES OR ONLY A GLOBAL MEASURE OF COGNITION, POTENTIALLY MASKING ANY SELECTIVE EFFECT ON EPISODIC MEMORY. AND IN OUR STUDY, WHICH I'M SHOWING YOU ON THE SLIDE HERE, WE FOUND THAT HAVING AT LEAST ONE E4 ALLELE WAS RELATED TO FASTER DECLINE IN EPISODIC MEMORY IN BOTH BLACKS AND WHITES, SHOWN IN THE TOP PANEL; BUT FOR OTHER DOMAINS OF COGNITIVE FUNCTION THERE WAS NO EFFECT OF E4 IN BLACKS, SHOWN IN THE BOTTOM PANEL. THIS IS IN CONTRAST WITH WHITES, WHERE E4 WAS RELATED TO FASTER DECLINE IN ALL DOMAINS OF COGNITIVE FUNCTION. SO, HERE YOU HAVE A RACIAL DIFFERENCE IN HOW E4 IS AFFECTING COGNITIVE DECLINE.WE ALSO HAVE EXAMINED A GENE ADJACENT TO APOE ON CHROMOSOME 19 CALLED TOMM40. MOST GENETIC STUDIES INCLUDE ONLY WHITES, AND THE TOMM40 GENE IS IN LINKAGE DISEQUILIBRIUM WITH E4 IN WHITES, SO IT'S BEEN THOUGHT THAT THIS GENE DOESN'T HAVE AN INDEPENDENT EFFECT BEYOND E4. BUT IF YOU LOOK AT THE CLUSTER OF TOMM40 HAPLOTYPES ACROSS RACE, YOU SEE A DIFFERENT PATTERN BETWEEN BLACKS AND WHITES. SO, AN E3 CARRIER, SHOWN ON THE LEFT, THE PATTERN IS SIMILAR ACROSS RACE FOR THESE HAPLOTYPES. BUT WE SEE A DIFFERENCE FOR E4 CARRIERS. FOR WHITE E4 CARRIERS, THERE ARE TWO CLUSTERS OF TOMM40 ALLELES WITHIN THE LONG RANGE, BUT BLACKS WITH E4 HAVE AN ADDITIONAL CLUSTER IN THE SHORT RANGE, SO THE QUESTION BECOMES, DOES THIS HETEROGENEITY IMPACT THE RISK OF ALZHEIMER'S OR COGNITIVE DECLINE IN BLACKS?AND THE ANSWER'S YES. WE EXAMINED THE RELATION OF APOE4 AND TOMM40 TO RISK OF ALZHEIMER'S DEMENTIA IN BLACKS AND WHITES IN OUR STUDIES. THE FIGURE ON THE LEFT SHOWS THE RESULTS FOR WHITES. APOE4 AND 523 LONG ALLELES ARE HIGHLY CONCORDANT SO EACH OF THE LINES ARE ON TOP OF EACH OTHER AND THERE IS AN ALMOST IDENTICAL AFFECT SIZE AND AFFECT PATTERN ON RISK OF ALZHEIMER'S FOR BOTH, WITH ABOUT A FOUR-FOLD INCREASE RISK FOR E4 AND 523 LONG HOMOZYGOTES, SHOWN BY THE TWO RED LINES. IN CONTRAST, THE PATTERN IS DIFFERENT FOR BLACKS. YOU LOOK AT THE TWO GRAPHS ON THE RIGHT, HERE WE SEE THAT THE LINKAGE BETWEEN E4 AND THE 523 LONG ALLELE IS WEAKER FOR BLACKS. IF YOU LOOK AT THE MIDDLE PANEL, THERE'S A STRONG ASSOCIATION OF E4 WITH INCIDENT ALZHEIMER'S SHOWN BY THE RED SOLID LINE, BUT WE DON'T SEE THE SAME INCREASE RISK FOR 523 LONG HOMOZYGOTES, THE RED DASHED LINE THAT WE DID FOR WHITES. SO, HERE YOU HAVE A NEIGHBORING GENE OF E4 THAT SEEMS TO FUNCTION DIFFERENTLY IN BLACKS THAN WHITES, SOMETHING YOU WOULDN'T BE AWARE OF WITHOUT INCLUDING BLACKS IN OUR STUDIES. THIS MIGHT ALSO EXPLAIN WHY E4 IN BLACKS IS WEAKER WHEN IT COMES TO ALZHEIMER'S, THE EFFECT OF E4 COULD VARY IN THIS POPULATION BASED ON WHAT TOMM40 VARIANT THEY HAVE.NEXT, WE EXAMINED THE EFFECT OF THE TOMM40 HAPLOTYPES ON COGNITIVE DECLINE. THE PLOT ON THE LEFT IS THE ONE YOU'VE SEEN BEFORE, REMINDING YOU OF THE DIFFERENT CLUSTERS ACROSS RACE. THE PLOT ON THE RIGHT SHOWS YOU THE RELATIONSHIP OF THE DIFFERENT HAPLOTYPES ON RATE OF DECLINE IN BLACKS AND WHITES. WHAT YOU CAN SEE IS THAT, BECAUSE OF LINKAGE DISEQUILIBRIUM, WHITES ONLY HAVE THE 523-LONG ALLELE, AND YOU CAN SEE THAT IT IS ASSOCIATED WITH A SIGNIFICANT RATE OF DECLINE SHOWN BY THE BLACK LINE. BLACKS, IN CONTRAST, HAVE BOTH THE LONG AND SHORT ALLELES, AND WHAT WE CAN SEE IS THAT THE 523 LONG, SHOWN BY THE GOLD COLOR LINE, IS ASSOCIATED WITH FASTER DECLINE AS IT IS IN WHITES, BUT BLACKS WITH EITHER ONE OR TWO 523 SHORT ALLELES, SHOWN BY THE RED AND BLUE LINES, HAVE A SLOWER RATE OF DECLINE. SO, IN THIS CASE IT'S THE 523 SHORT ALLELE THAT'S ACTUALLY PROTECTIVE FOR DECLINE.AND WHAT IF WE LOOK AT PATHOLOGY? IN ONE STUDY OF BLACKS AND WHITES WHO WERE RECRUITED FROM OUR MEMORY CLINIC AND DIED AND CAME TO AUTOPSY, WE COMPARED THE FREQUENCY OF UNDERLYING PATHOLOGY IN PEOPLE WHO PRESENTED TO US WITH DEMENTIA. THESE PIE CHARTS SHOW YOU THE PROPORTION OF BLACKS AND WHITES WITH THE DIFFERENT PATHOLOGIES, BLACKS ARE ON THE LEFT AND WHITES ARE ON THE RIGHT. WE FOUND THAT BLACKS WERE MORE LIKELY TO HAVE MIXED PATHOLOGY AS A CAUSE OF THEIR DEMENTIA, SHOWN BY THE RED PIE SLICE, COMPARED TO WHITES, WHO WERE MORE LIKELY TO HAVE ALZHEIMER'S DISEASE AS A CAUSE FOR THEIR DEMENTIA.LET'S MOVE TO WHAT WE KNOW ABOUT BIOMARKERS. I KNOW WE'RE ALL FAMILIAR WITH THE RESEARCH FRAMEWORK FOR ALZHEIMER'S THAT RELATES TEMPORAL CHANGES IN AD BIOMARKERS TO CLINICAL DISEASE STAGE. A MODEL THAT WAS DEVELOPED BASED ON STUDIES OF PRIMARILY WHITES. WHAT DO WE KNOW ABOUT THESE BIOMARKERS IN DIVERSE POPULATIONS? WELL, THERE'S RELATIVELY LESS DATA ON AD BIOMARKERS IN DIVERSE POPULATIONS COMPARED TO STUDIES OF WHITES. I'M SHOWING YOU HERE THIS TABLE OF EMERGING LITERATURE IN THIS SPACE, AND ALTHOUGH THE SAMPLE SIZES TEND TO BE SMALL AND, IN SOME CASES, NON-REPRESENTATIVE, A GROWING NUMBER OF STUDIES SUGGEST THAT TAU MAY BE LOWER IN BLACKS. ONE STUDY FOUND THAT AMYLOID MAYBE BE HIGHER, AND ANOTHER STUDY FOUND NO DIFFERENCE IN ANY BIOMARKER BY RACE AND ETHNICITY. CLEARLY MORE STUDIES ARE NEEDED TO GATHER BIOMARKER DATA IN DIVERSE POPULATIONS, BUT THE QUESTION THAT I HAVE WHEN I SEE THIS TABLE OF RESULTS IS, DOES THE ATN FRAMEWORK NEED TO BE REEVALUATED OR REVISED TO TAKE INTO ACCOUNT THESE DIFFERENT PATTERNS? THE PROBLEM IS, IF WE CONTINUE TO USE A FRAMEWORK THAT HAS BEEN DEVELOPED WITH DATA ONLY FROM ONE POPULATION, HOW DO WE INTERPRET THE RESULTS IN DIVERSE POPULATIONS? I THINK WE NEED MORE DATA AND THE ATN FRAMEWORK NEEDS TO BE TESTED WITH DATA FROM DIVERSE POPULATIONS IS THE SHORT STORY.AND, WE HAVE TO REMEMBER THAT NO ONE HAS JUST ONE DISEASE. OLDER ADULTS OFTEN HAVE MULTIPLE DISEASES AND MANY OF THESE DISEASES ALSO AFFECT COGNITION. THEY SHOW DISPARITIES. SO, HERE ARE RECENT DATA, AGAIN FROM THE NORTHERN MANHATTAN STUDY, THAT SHOWS AN INCREASED RISK FOR DIFFERENT STROKE SUBTYPES AMONG BLACKS AND HISPANICS COMPARED TO WHITES. WE CAN LOOK AT HIV; WE KNOW THAT HIV AFFECTS COGNITION AND HERE WE SEE THAT LATINOS WITH HIV HAVE AN INCREASED RISK OF COGNITIVE IMPAIRMENT COMPARED TO NON-LATINO WHITES WITH HIV. THE STUDY ALSO HIGHLIGHTED THAT THERE ARE IMPORTANT DIFFERENCES AMONG LATINO SUBGROUPS, AND ONE RELEVANT WAY IN WHICH LATINOS DIFFER IS BASED ON THEIR COUNTRY OF ORIGIN. IN THIS STUDY, HIV-POSITIVE PUERTO RICANS HAD A HIGHER RISK OF COGNITIVE IMPAIRMENT THAN HIV-POSITIVE MEXICANS.AND FOR A MORE TIMELY EXAMPLE, A RECENT STUDY BY WANG ET AL. THAT DID A RETROSPECTIVE CASE CONTROL ANALYSIS OF PATIENT ELECTRONIC HEALTH RECORDS SHOWED THAT PATIENTS WITH DEMENTIA WERE AT INCREASED RISK FOR COVID-19 COMPARED TO PATIENTS WITHOUT DEMENTIA, WITH THE STRONGEST EFFECTS FOR VASCULAR DEMENTIA. AND IN THIS STUDY, THERE WAS A STARK DISPARITY, AS SHOWN IN THE SLIDE HERE, BLACKS WITH DEMENTIA WERE AT EVEN GREATER RISK OF COVID-19 THAN WHITES WITH DEMENTIA. THESE AUTHORS REPORTED A SIMILAR RACIAL DISPARITY FOR COVID-19 RISK BEFORE AND AFTER CONTROLLING FOR COVID-19 RISK FACTORS, SUGGESTING THAT FACTORS OTHER THAN STRICTLY MEDICAL CONDITIONS, INCLUDING ACCESS TO HEALTH CARE, SOCIOECONOMIC STATUS, AND SOCIAL ADVERSITY MAY HAVE CONTRIBUTED TO THIS RACIAL DISPARITY.SO, LIKE THE COVID EXAMPLE, MOST OF THESE DISPARITIES IN DEMENTIA ARE LIKELY DUE TO DIFFERENCES IN SOCIAL DETERMINANTS OF HEALTH. AND AS DISCUSSED EARLIER, WE KNOW THAT THESE FACTORS SHAPE HEALTH AND HEALTH OUTCOMES IN POWERFUL WAYS, YET THEIR ROLE IN STUDIES OF DEMENTIA AND COGNITIVE IMPAIRMENT ARE RELATIVELY UNDERSTUDIED. FURTHER, THESE SOCIAL DETERMINANTS CAN OPERATE AT DIFFERENT POINTS ACROSS THE LIFE COURSE. THIS SLIDE SHOWS EXAMPLES OF FINDINGS FROM DIFFERENT STUDIES IN THE FIELD THAT HAVE -- THAT HAVE DEMONSTRATED UPSTREAM AND DOWNSTREAM EFFECTS OF VARIOUS SOCIAL DETERMINANTS AND THEIR IMPACT ON COGNITION OR RISK OF DEMENTIA. IT HAS BECOME AN INCREASINGLY CLEAR THAT JUST LIKE THE ACCUMULATION OF PATHOLOGY THAT WE NOW KNOW IS OCCURRING DECADES BEFORE THE APPEARANCE OF CLINICAL SYMPTOMS, THERE'S ALSO A LIFE COURSE ACCUMULATION OF RISKS AND RESILIENCE FACTORS THAT INTERACT WITH EACH OTHER AND ULTIMATELY INFLUENCE DISEASE IN LATE LIFE.SO, LET'S TAKE IT BACK TO COGNITION. WE HAVE STRONG EVIDENCE FROM NUMEROUS STUDIES OVER THE YEARS THAT DIVERSE OLDER ADULTS TEND TO PERFORM MORE POORLY ON OUR COGNITIVE FUNCTION TESTS, ON AVERAGE, THAN THEIR AGE-MATCHED WHITE COUNTERPARTS. BUT WE KNOW THAT COGNITIVE FUNCTION IS INFLUENCED BY MULTIPLE FACTORS OUTSIDE OF COGNITION ITSELF AND THESE FACTORS ALSO TEND TO VARY BY RACE AND ETHNICITY, YET FEW STUDIES ACCOUNT FOR THESE FACTORS WHEN DOING COMPARISON STUDIES. ONE OF THE KEY RECOMMENDATIONS FROM PAST SUMMITS HAS BEEN TO UNDERSTAND ALL ASPECTS OF HEALTHY BRAIN AGING AND COGNITIVE RESILIENCE TO INFORM STRATEGIES FOR ALZHEIMER'S PREVENTION. I WANT TO ARGUE THAT IN ORDER TO ENABLE PRECISION MEDICINE FOR ALZHEIMER'S TREATMENT AND PREVENTION, WE MUST CENTER DIVERSITY. IT IS TIME TO STOP USING DEFICIT-BASED THINKING TO UNDERSTAND HOW OUR DIVERSE PARTICIPANTS DIFFER FROM THE MAJORITY WHITE POPULATION. INSTEAD, LET'S LEVERAGE THE LIVED EXPERIENCE OF PARTICIPANTS, PARTICULARLY DIVERSE PARTICIPANTS TO MEASURE AND UNDERSTAND THE WAYS IN WHICH SOCIAL DETERMINANTS PLAY A ROLE IN AGING AND RISK OF DISEASE.IN THE NEXT SERIES OF SLIDES, I WANT TO PROVIDE A FEW EXAMPLES OF WHAT I MEAN BY CENTERING DIVERSITY AND SHOWING HOW THE LIVED EXPERIENCE CAN HAVE AN IMPACT ON BRAIN HEALTH FOR OLDER BLACKS. IN ONE OF OUR STUDIES, WE EXAMINED THE EFFECT OF GEOGRAPHIC PLACE OF BIRTH ON LATE-LIFE COGNITION. ALL OF OUR PARTICIPANTS LIVE IN CHICAGO NOW, BUT WE ASKED THEM WHERE THEY WERE BORN AND WHERE THEY WERE LIVING AT AGE 12. CONSISTENT WITH PREVIOUS STUDIES THAT HAVE SHOWN ADVERSE HEALTH EFFECTS FOR SOUTHERN U.S. BIRTH, WE FOUND THAT PARTICIPANTS WHO WERE BORN IN THE SOUTH OR LIVING IN THE SOUTH AT AGE 12 HAD OVERALL LOWER PERFORMANCE ON OUR COGNITIVE FUNCTION TESTS GIVEN TO THEM DURING LATE LIFE. THIS EXPOSURE DID NOT PREDICT CHANGE OVER TIME, HOWEVER.WE ALSO KNOW THAT SOCIOECONOMIC STATUS IS AN IMPORTANT SOCIAL DETERMINANT FOR BRAIN HEALTH. THESE ARE DATA FROM THE HEALTH ABC STUDY BY YAFFE AND COLLEAGUES, SHOWING THAT BLACKS WITH LESS THAN A HIGH SCHOOL EDUCATION HAVE A HIGHER RISK OF DEMENTIA THAN WHITES WITH LESS THAN HIGH SCHOOL. BUT WHAT DO WE KNOW ABOUT THE EDUCATIONAL EXPERIENCE OF BLACKS IN THIS AGE COHORT? WELL, WE KNOW THAT BLACKS IN THE AGE GROUP THAT WE'RE WORKING WITH NOW REPRESENT THE FIRST GENERATION OF BLACKS TO ATTEND LEGALLY DESEGREGATED SCHOOLS AFTER THE BROWN V. BOARD OF EDUCATION DECISION IN 1954. WE ASKED PARTICIPANTS ABOUT THEIR EXPERIENCE ATTENDING SEGREGATED SCHOOLS IN EARLY LIFE AND WE FOUND THAT INTERACTION OF PLACE OF BIRTH AND SCHOOL SEGREGATION -- THOSE BORN IN THE SOUTH WHO ATTENDED LEGALLY DESEGREGATED SCHOOLS HAD THE LOWEST PERFORMANCE OF ALL OTHER GROUPS, INCLUDING THOSE BORN IN THE SOUTH WHO ATTENDED SEGREGATED SCHOOLS. THIS WAS AN UNEXPECTED FINDING GIVEN THAT SEGREGATED SCHOOLS DURING THAT TIME OFTEN LACKED ESSENTIAL RESOURCES AND WERE THOUGHT TO BE INFERIOR TO THE ALL-WHITE SCHOOLS. IT'S PLAUSIBLE THAT THIS EXPERIENCE OF INTEGRATING SCHOOLS IN EARLY LIFE, DURING A TUMULTUOUS RACIAL CLIMATE IN THE DEEP SOUTH, SERVED AS AN EARLY LIFE STRESSOR FOR BLACKS AND 40 TO 50 YEARS LATER, WE SEE THE IMPACT OF THIS STRESS ON COGNITIVE FUNCTION.THIS WOULD CERTAINLY BE CONSISTENT WITH THE ABUNDANT RESEARCH IN WHITES THAT SHOWS A NEGATIVE IMPACT OF EARLY LIFE STRESS ON LATE LIFE HEALTH AND COGNITION. AND WE HAVE DATA FROM ANOTHER STUDY THAT IS CONSISTENT WITH THIS IDEA THAT THE EXPLANATORY MECHANISM COULD BE LINKED TO STRESS. IN ANOTHER STUDY WE LOOKED AT THE RELATIONSHIP OF PERCEIVED STRESS, USING A SCALE THAT MEASURES THE DEGREE TO WHICH A PERSON FINDS THEIR LIVES UNPREDICTABLE, UNCONTROLLABLE, AND OVERLOADING, AND WE FOUND THAT BLACKS WHO REPORTED HIGHER PERCEIVED STRESS HAD FASTER RATES OF COGNITIVE DECLINE, PARTICULARLY FOR EPISODIC MEMORY AND VISUAL-SPATIAL ABILITY. ANOTHER PERSISTENT LIVED EXPERIENCE THAT HAS GARNERED GREATER ATTENTION SINCE THE PANDEMIC AND PUBLIC DEATH OF GEORGE FLOYD IS THE EXPERIENCE OF DISCRIMINATION FOR BLACK AND BROWN PEOPLE. DISCRIMINATION AS A RISK FACTOR FOR POOR HEALTH HAS BEEN SHOWN IN NUMEROUS STUDIES, LONG BEFORE THE PANDEMIC. USING A VALIDATED SCALE THAT ASKS ABOUT COMMON EXPERIENCES OF UNFAIR TREATMENT AND MICROAGGRESSIONS WE EXAMINED THE ASSOCIATION OF DISCRIMINATION WITH COGNITION IN OUR COHORT OF OLDER BLACKS AND FOUND THAT HIGHER REPORTS OF DISCRIMINATION WERE ASSOCIATED WITH POOR PERFORMANCE ON COGNITIVE FUNCTION, PARTICULARLY TESTS OF EPISODIC MEMORY AND PERCEPTUAL SPEED.IN A SEPARATE STUDY, WE FOUND THAT PEOPLE REPORTING MORE DISCRIMINATION ALSO HAD HIGHER LEVELS OF C-REACTIVE PROTEIN IN THEIR BLOOD, IN A DOSE-RESPONSE FASHION, SUGGESTING INFLAMMATION AS A -- AS ONE POTENTIAL BIOLOGIC MECHANISM LINKING DISCRIMINATION TO POOR COGNITION. WE ALSO FOUND A NEUROBIOLOGIC FOOTPRINT OF DISCRIMINATION, USING RESTING STATE FMRI WE FOUND THAT HIGHER LEVELS OF DISCRIMINATION WERE ASSOCIATED WITH DIFFERENTIAL INSULA FUNCTIONAL CONNECTIVITY, SPECIFICALLY HIGHER DISCRIMINATION WAS ASSOCIATED WITH DIFFERENTIAL CONNECTIVITY IN THE SAME AREAS THAT ARE INVOLVED IN TRUST PERCEPTION. AND IN NEW DATA HOT OFF THE PRESSES, WE FOUND THAT IN THOSE BLACKS WHO DIED AND CAME TO AUTOPSY, THOSE WHO REPORTED MORE DISCRIMINATION HAD MORE VESSEL DISEASE, ATHEROSCLEROSIS AND ARTERIOLOSCLEROSIS, THAN THOSE WITH LOWER REPORTS OF DISCRIMINATION. INTERESTINGLY, DISCRIMINATION WAS NOT RELATED TO AD PATHOLOGY IN THIS SAMPLE. THINKING BACK TO THE EARLIER STUDY WHERE I SHOWED YOU THE INCREASED HETEROGENEITY OF PATHOLOGY IN BLACKS WITH DEMENTIA, THIS STUDY SHOWS HOW A RISK MARKER OF A LIVED EXPERIENCE CAN BE DIFFERENTIALLY ASSOCIATED WITH ONE OF THE PATHOLOGIC MARKERS THAT WE KNOW UNDERLIE DEMENTIA.AND FINALLY, WE HAVE DATA ON A SOCIAL CONSTRUCT CALLED JOHN HENRYISM, MEASURED WITH A SCALE DEVELOPED BY SHERMAN JAMES, A NOTED EPIDEMIOLOGIST AND RACE SCHOLAR. JOHN HENRYISM IS A STRATEGY FOR COPING WITH PROLONGED EXPOSURE TO STRESSORS LIKE DISCRIMINATION AND HAS BEEN LINKED WITH HIGHER CARDIOVASCULAR DISEASE, PRIMARILY IN BLACK MEN. IN THIS STUDY, BY ONE OF OUR POSTDOCS, WE SEE THAT HIGHER REPORTS OF JOHN HENRYISM IS ASSOCIATED WITH LOWER COGNITION, AN EFFECT THAT IS SIMILAR IN IMPACT TO HAVING FEWER YEARS OF EDUCATION. SO, BY CENTERING DIVERSITY AND LOOKING AT THE TOTALITY OF THESE LIVED EXPERIENCES, WE WILL BE ABLE TO WORK OUR WAY DOWN FROM THE EXPOSOME, THE VARIETY OF RISK FACTORS ACROSS THE LIFE SPAN THAT REFLECT THE LIVED EXPERIENCE OF OUR DIVERSE POPULATIONS, ALL THE WAY DOWN TO THE QUANTITATIVE CLINICAL PHENOTYPE AND ULTIMATELY TO THE SYNDROMIC PHENOTYPE OF DEMENTIA TO HELP US UNDERSTAND THE ROOT CAUSE OF THE DISPARITIES WE SEE ACROSS POPULATIONS.AND FOR ME, THESE RECENT DATA FROM FOCUS GROUPS CONDUCTED BY THE ALZHEIMER'S ASSOCIATION UNDERSCORE THE IMPORTANCE OF CENTERING DIVERSITY. WE ALREADY KNOW THAT THERE ARE SIGNIFICANT BARRIERS TO INCLUSION IN CLINICAL AD RESEARCH, BUT THIS EMPHASIZES THAT A MAJOR BARRIER FOR US AS RESEARCHERS IS EARNING THE TRUST OF PEOPLE OF COLOR. 62 PERCENT OF BLACK ADULTS BELIEVE THAT MEDICAL RESEARCH IS BIASED AGAINST PEOPLE OF COLOR, AND ONLY ABOUT A HALF BELIEVE THAT AN ALZHEIMER'S CURE WILL BE SHARED EQUALLY REGARDLESS OF RACE, COLOR, OR ETHNICITY. IS THERE ANY WONDER THAT WE STRUGGLE TO MEET RECRUITMENT GOALS IN OUR STUDIES, ESPECIALLY OUR CLINICAL TRIALS?AS RESEARCHERS, IT IS UP TO US TO CHANGE THESE PERCEPTIONS. IT WILL REQUIRE US TO CENTER DIVERSITY, TO ASK QUESTIONS THAT ARE RELEVANT TO A PARTICULAR COMMUNITY, TO DIVERSIFY THE WORKFORCE SO THAT WE BRING IN DIFFERENT PERSPECTIVES AND NARRATIVES AND TO STOP MAKING ASSUMPTIONS ABOUT THIS DISEASE BASED ON DATA FROM ONE POPULATION. BASICALLY, WE HAVE TO DO MORE TO BECOME TRUSTWORTHY AS RESEARCHERS.ONE DISPARITY THAT I HAVEN'T TOUCHED ON, BUT WE'LL HEAR A LOT ABOUT THROUGHOUT THE SUMMIT IS SEX DIFFERENCES. ALZHEIMER'S IS A WOMAN'S DISEASE, TWO THIRDS OF PEOPLE IN THE U.S. LIVING WITH AD ARE WOMEN, IT'S THE FIFTH LEADING CAUSE OF DEATH IN WOMEN. TWO THIRDS OF CAREGIVERS FOR ALZHEIMER'S PATIENTS ARE WOMEN AND THEY SPEND MORE TIME IN THE CAREGIVING ROLE, YET WE KNOW VERY LITTLE ABOUT HOW SEX INTERACTS WITH THE TYPES OF SOCIAL DETERMINANTS ACROSS RACE AND ETHNICITY THAT I'VE SHOWN YOU TODAY. THIS IS ANOTHER AREA OF RESEARCH WHERE WE NEED MUCH MORE DATA.SO, WE'VE COME TO THE END OF THE ROAD, I HOPE YOU'VE LEARNED SOMETHING ON THIS ROAD TRIP AND HAVE MORE IN YOUR TOOLKIT ABOUT WHAT IS NEEDED TO ACHIEVE ADVANCES ON THE PATH TO PRECISION MEDICINE. IT IS CLEAR THAT WE NEED MORE DATA, ESPECIALLY IN THOSE CASES WHERE WE DON'T EVEN KNOW IF A DISPARITY EXISTS. BUT FULLY REALIZING THIS GOAL OF PRECISION MEDICINE WILL REQUIRE A SHIFT IN OUR THINKING. IT WILL REQUIRE US TO BECOME MORE INCLUSIVE, TO ASK NEW QUESTIONS AND TO UNDERSTAND THE LIVED EXPERIENCE ACROSS THE ENTIRE LIFESPAN OF ALL OF OUR PARTICIPANTS. IT WILL REQUIRE US TO CENTER DIVERSITY. THANK YOU AND ENJOY THE REST OF THE SUMMIT. WELL, IT'S A PLEASURE TO BE WITH EVERYONE. I WANT TO THANK THE ORGANIZERS FOR INVITING ME TO GIVE THIS TALK, AND I WANT TO THANK THEM, ALSO, FOR ORGANIZING WHAT IS ALWAYS AN INCREDIBLE MEETING. AND WHILE IT'S A SHAME WE CAN'T ALL GET TOGETHER IN PERSON, I'M SO HAPPY THAT WE'RE ABLE TO CONNECT AND GO THROUGH SUCH AN IMPORTANT TOPIC AND CONNECT AS A COMMUNITY.SO, A NUMBER OF YOU WILL KNOW ME. MY NAME'S NATHAN PRICE. I'VE BEEN WITHIN THE AMP-AD CONSORTIUM FOR THE PAST SEVEN YEARS AS A PROFESSOR AT THE INSTITUTE FOR SYSTEMS BIOLOGY. AS YOU MAY NOT KNOW, I RECENTLY SWITCHED ROLES, AND I'M NOW CEO OF COMPANY CALLED ONEGEVITY; IT'S A DIVISION OF THORNE HEALTHTECH. SO, THAT'S MY NEW ADDRESS, BUT I MAINTAIN, ALSO, AN ON-LEAVE BY COURTESY APPOINTMENT AT ISB WITH THE LAB. SO, TODAY I'M GOING TO TALK ABOUT MECHANISTIC INSIGHTS AND TECHNOLOGIES FOR PRECISION MEDICINE RESEARCH ON AGING AND ALZHEIMER'S. SO, I HARDLY NEED TO SAY IN THE CONTEXT OF THIS COMMUNITY ANYTHING ABOUT ALZHEIMER'S DISEASE, BUT I'LL JUST SAY A FEW WORDS IN FRAMING, JUST AS WE THINK AGAIN ABOUT THE IMMENSE HEALTH AND SCIENTIFIC CHALLENGE THAT IS BEFORE US. ALZHEIMER'S IS OBVIOUSLY MASSIVELY COSTLY TO SOCIETY IN HUMAN TRAGEDY AND IN TERMS OF ITS ECONOMIC IMPACT. IT'S A HIGHLY COMPLEX AND HETEROGENEOUS DISEASE. WE HAVE PRETTY LIMITED SAMPLES BEFORE DEATH. IT'S NOT LIKE CANCER, WHERE WE GET TUMORS THAT ARE TAKEN OUT OF THE PERSON AS THEY GO ALONG. THAT MAKES PERIPHERAL MEASURES, SUCH AS OUT OF THE BLOOD AND IMAGING, ABSOLUTELY ESSENTIAL TO ALL THAT WE DO. THE LONG TIME SCALES OF ALZHEIMER'S ALSO MAKE IT DIFFICULT AND COSTLY TO TRACK BOTH THE INITIATION AND THE DEVELOPMENT OF THE DISEASE. EARLY INTERVENTIONS ARE CLEARLY CRITICAL BEFORE LARGE-SCALE NEURONAL DEATH HAS BEGUN. AND THIS MAY BE ONE OF THE REASONS WHY LIFESTYLE TRIALS AIMED AT PREVENTION HAVE BEEN THE MOST EFFICACIOUS TO DATE, THE FINGER STUDY BEING THE CLASSIC EXAMPLE. AND EFFECTIVE DRUG TREATMENTS THAT WE ALL WANT HAVE REMAINED ELUSIVE TO DATE.SO, THE ALZHEIMER'S DISEASE RESEARCH COMMUNITY IS RISING TO THE CHALLENGE, AND THE NIH AND THE NIA HAVE PUT IN MASSIVE INVESTMENTS IN ORDER TO MAKE THIS POSSIBLE. GIVEN THE MULTI-DECADE TIME SCALES, THE DIVERSITY, AND THE COMPLEXITY OF THIS DISEASE, IT'S CLEAR THAT WE NEED A LOT OF DENSE LONGITUDINAL DATA. WE NEED SYSTEMS APPROACHES TO INTERPRET AND INTEGRATE THOSE DATA, AND WE NEED WAYS TO GET AT CAUSALITY THROUGH EXPERIMENTATION ANALYSIS. AND THESE ARE THE PIECES THAT HAVE BEEN PUT TOGETHER WITHIN THE NIA WITH A NUMBER OF IMPRESSIVE INITIATIVES, MANY OF WHICH I HAVE SHOWN HERE ON THE RIGHT. AND THE CHALLENGE THAT I WANT TO ADDRESS TODAY AND TRY TO TAKE, AT LEAST, A STEP TOWARDS IS WHAT CAN WE DO NOW TO EFFECTIVELY ANALYZE OUR EXISTING AND EMERGING DATA AND GO FROM SNAPSHOTS TO A MECHANISTIC AND DYNAMIC VIEW OF THIS TERRIBLE DISEASE.BEFORE I REALLY DIVE IN, THOUGH, I'M GOING TO DO ONE MORE BIT OF PREAMBLE, WHICH IS JUST TO SAY A NOTE ABOUT AGING. AGING IS OBVIOUSLY A MAJOR RISK FACTOR FOR ALZHEIMER'S DISEASE. ONE OF THE ELEMENTS WE HAVE TO THINK ABOUT A LOT AS WE GO THROUGH OUR RESEARCH, AND WHY IT APPEARS -- WELL, WHY ALZHEIMER'S APPEARS LATE IN LIFE. I'LL JUST SHOW ONE EXAMPLE. THIS IS FROM OUR OWN WORK, RECENTLY. I'M SURE THERE'S A HUNDRED OTHER EXAMPLES THAT COULD COME FROM PEOPLE IN THE AUDIENCE AND IN THE SUMMIT, BUT HERE, THIS WAS AN ANALYSIS WE DID ON THE MICROBIOME THAT SHOWED THAT, ACTUALLY, AS YOU GO OLDER, STARTING IN ABOUT YOUR AGE AROUND 40S OR 50S, MICROBIOMES START BECOMING INCREASINGLY UNIQUE; EACH PERSON'S MICROBIOME BECOMES MORE DIFFERENT THAN ANYONE ELSE'S MICROBIOME. AND IF YOU STAY HEALTHY, THAT'S A TREND THAT CONTINUES THROUGHOUT LIFE. AND THERE ARE MANY -- AND I'M NOT GOING TO GET IN THE DETAILS ON THIS OTHER THAN JUST TO SAY THERE ARE MANY, MANY SUCH FACTORS THAT ARE CHANGING IN AGE, AND HOW DO WE SUS THROUGH SO MANY OF THESE DIFFERENT FACTORS TO FIGURE OUT WHICH ARE THE ONES THAT ARE MOST IMPORTANT TO THE ALZHEIMER'S PROCESS. AND YOU WILL HEAR MORE ABOUT THE POTENTIAL LINKS BETWEEN THE MICROBIOME AND ALZHEIMER'S IN A SESSION THAT'S COMING LATER WHERE ROB KNIGHT, AND BEN READHEAD, AND OTHERS WILL BE SPEAKING TO THAT TOPIC.ALL RIGHT. SO, I'M GOING TO JUMP IN NOW. I'M GOING TO SHARE THREE VIGNETTES WITH YOU ON SOME OF THE WAYS THAT WE CAN INTEGRATE DATA TO TRY TO FIND INSIGHTS THAT ARE RELEVANT TO ALZHEIMER'S DISEASE. THE FIRST OF THESE IS WORK THAT WAS LED BY LAURA HEATH WHEN SHE WAS IN MY RESEARCH GROUP. SHE'S NOW A RESEARCH SCIENTIST AT SAGE. THIS WORK WAS SUPPORTED BY THE NIA THROUGH THE AMP-AD PROGRAM. THIS WAS WORK THAT WAS CARRIED OUT WITH TWO REALLY WONDERFUL LONGTIME COLLABORATORS, TODD GOLDE AND NIL FER ERTEKIN-TANER, WHO WERE JUST SUCH A JOY TO WORK WITH FOR THE LAST SEVEN YEARS. AND I'M GOING TO TALK TO YOU ABOUT THIS PAPER, WHICH IS ABOUT THE MANIFESTATION OF AD GENETIC RISK IN THE BLOOD, AND HOW WE CAN USE CLUES FROM THOSE GENETIC ANALYSES TO LOOK FOR PRE-SYMPTOMATIC EFFECTS AND THE ORIGINS OF DISEASE INITIATION.SO, THANKS TO THE WORK OF SO MANY WHO ARE AT THE SUMMIT AND ACROSS, IN PARTICULAR, THE IGAP CONSORTIUM, WE HAVE A LARGE AMOUNT OF KNOWN ALZHEIMER'S DISEASE RISK-ASSOCIATED VARIANTS, AND YOU CAN SEE THOSE HERE. THERE'S A WHOLE BUNCH OF THEM THAT HAVE SMALL EFFECT SIZES, APOE AND APOE 4 IS THE HIGH-RISK VARIANT, IS THE MOST FAMOUS ONE HAS THE LARGEST EFFECT OF THOSE THAT ARE BROAD IN THE POPULATION. THERE ARE A NUMBER OF GENES THAT ARE IMPLICATED THAT ARE INVOLVED IN LIPID METABOLISM, ENDOCYTOSIS, AND IMMUNE FUNCTION. AND ALL THE GENETICS THAT I'M GOING TO SHOW IN THIS TALK, THE STARTING POINT, AT LEAST, THE GENETICS THAT WE USE COME FROM THIS KUNKLE, ET AL, PAPER IN NATURE GENETICS IN 2019.SO, WHAT WE'RE GOING TO DO HERE IS WE'RE GOING TO UTILIZE A RESOURCE THAT WE HAVE, WHICH COMES FROM THE ARIVALE DATA SET. ARIVALE WAS A COMPANY THAT LEE HOOD AND I CO-FOUNDED SOME YEARS AGO. IT'S GONE OUT OF BUSINESS; THERE'S NO FINANCIAL COI, BUT WE DO HAVE A LOT OF DATA THAT COMES FROM THERE THAT HAS USEFULNESS IN A WIDE VARIETY OF SETTINGS, AND WE'VE UTILIZED IT HERE UNDER SUPPORT FROM A SUPPLEMENT GRANT FROM AMP-AD. AND SO, WHAT WE DID HERE WAS WE HAD OVER 2,800 PARTICIPANTS THAT WE HAD WHOLE GENOME SEQUENCING ON, AND WE HAD OVER 1,200 ANALYTES, CLINICAL CHEMISTRIES, PROTEOMICS, METABOLOMICS, DEMOGRAPHICS, LIFESTYLE, HEALTH HISTORY, A WHOLE BUNCH OF INFORMATION. AND ALL WE'RE DOING IS ANALYZING THOSE DATA IN THE CONTEXT OF EACH OF THE GENETIC RISK FACTORS FOR ALZHEIMER'S DISEASE TO LOOK FOR ALTERED BIOLOGICAL FUNCTIONS THAT MIGHT CAPTURE DIFFERENCES IN THE POPULATION WELL BEFORE ANY SYMPTOMS ARRIVE. SO, THIS IS OVER ALL THE DECADES OF ADULTHOOD, AND SEE IF WE CAN SEE SIGNALS THAT ARE RELATED TO THAT. SO, THIS IS THE RESULT OF THAT ANALYSIS. ALL THE DETAILS -- BECAUSE I'M GOING TO BE PRETTY BRIEF HERE TODAY, ALL THE DETAILS ARE IN THIS BIORXIV PAPER, SO IT'S SUBMITTED TO A JOURNAL AND IS IN BIORXIV, WHERE YOU CAN READ IT, IF YOU'D LIKE. BUT WHAT WE SEE IS THAT THERE ARE, INDEED, STATISTICALLY SIGNIFICANT ASSOCIATIONS FOUND WITH FIVE OF THESE SNPS WHERE WE SEE ALTERATIONS IN EITHER PROTEINS OR METABOLITES THROUGH THE COURSE OF ADULTHOOD IN INDIVIDUALS WHO ARE ASYMPTOMATIC. THESE ARE GENES INVOLVED IN LIPID METABOLISM AND HOMEOSTASIS, AND THE ONE I'LL HIGHLIGHT THE MOST HERE IS IN CELL SIGNALING, INPP5D. NOW, INPP5D IS AN INTERESTING EXAMPLE IN PART BECAUSE IT'S BEEN NOMINATED BY THREE DIFFERENT TEAMS IN AMP-AD: THE DUKE TEAM, LED BY RIMA KADDURAH-DAOUK; THE TEAM I HAVE BEEN A PART OF FOR MANY YEARS, THE MAYO/ISBU/UNIVERSITY OF FLORIDA TEAM; AND ALSO BIN ZHANG'S TEAM AT MOUNT SINAI. SO, THAT'S BEEN PUT FORTH AND BEEN ADVANCED INTO DRUG DISCOVERY. YOU'RE GOING TO HEAR MORE ABOUT THIS IN AD SUMMIT SESSION THREE ON THE TREAT AD CENTERS. BUT WHAT'S INTERESTING OUT OF THIS ANALYSIS IS THAT WE DO FIND THAT THERE IS A PROTEIN, IDUA, WHICH IS SIGNIFICANTLY DIFFERENT IN INDIVIDUALS WELL BEFORE SYMPTOMS THAT IS A FUNCTION OF THIS PARTICULAR GENE VARIANT. SO, IT DOES SUGGEST THAT THIS GENE VARIANT MAY BE HAVING A ROLE VERY EARLY ON IN THE DISEASE. WE DON'T KNOW THAT; BUT IT'S JUST A SIGN THAT MAYBE SOMETHING IS HAPPENING WELL INTO THE VERY BEGINNINGS OF THIS PROCESS.A SECOND VERSION THAT I'LL GO THROUGH, OR A SECOND FINDING FORM THIS PAPER, CENTERS AROUND PILRA AND PILRB. SO, AS WE ALL KNOW, ALZHEIMER'S TAKES DECADES TO EMERGE, AND WHAT THIS SHOWS IS -- THIS IS BREAKING IT DOWN NOW BY AGE GOING FROM ACROSS ALL OF ADULTHOOD FROM 18 UP TO 70-PLUS HERE. AND IT LOOKS AT THE LEVELS OF PILRA AND PILRB IN THE BLOOD AROUND A SNP THAT WAS FOUND PREVIOUSLY AT THE NYAP1 LOCUS. AND WHAT'S INTERESTING HERE IS THAT THERE WAS AN EARLIER STUDY THAT SUGGESTED THAT THE CAUSAL SNP MAY NOT ACTUALLY BE A NYAP1, BUT RATHER IN PILRA, WHICH WAS LINKAGE DISEQUILIBRIUM, THESE RESULTS SUPPORT THAT IDEA, AS WELL. SO, JUST MORE EVIDENCE FOR THAT, AND SHOWING THAT THERE IS, IN FACT, A DIFFERENCE BETWEEN INDIVIDUALS WHO ARE AT HIGHER AND LOWER RISK FOR ALZHEIMER'S DISEASE IN THE CONCENTRATION OF THIS MOLECULE 1AS A PROTEIN IN THE BLOOD.SO, A F1INAL ELEMENT FROM THIS STUDY THAT I'LL MENTION IS JUST THAT GENETIC VARIATION DOES EFFECT MEN AND WOMEN DIFFERENTLY, AND IF WE LOOK AT THE INTERACTION TERMS BETWEEN THE GENETICS AND HOW IT PREDICTS A CHANGE IN -- OR HOW IT'S ASSOCIATED WITH A CHANGE IN THE ANALYTE LEVELS IN THE BLOOD, WE FIND ONE REALLY INTERESTING EXAMPLE HERE, WHICH IS PICALM, WHICH SHOWS A BUNCH OF ANALYTES WHERE THEY ACTUALLY MOVE UP IN MEN AND DOWN IN WOMEN, OR VICE-VERSA. AND SO, IT'S HAVING AN EFFECT ON SOME OF THE SAME MOLECULES, BUT IN THE OPPOSITE DIRECTION. SO, WE THEN ASK THE IGAP CONSORTIUM -- AND BRIAN KUNKLE RAN THIS ANALYSIS, JUST TO LOOK AND SEE IF, IN FACT, THERE WAS A DIFFERENCE IN THE GENETIC RISK AT THE PICALM VARIANT BETWEEN MEN AND WOMEN. AND IN FACT, THERE IS, AND YOU CAN READ MORE ABOUT THAT, AGAIN, IN THE PAPER.OKAY. SO, THAT'S THE END OF THE FIRST STORY. SO, IN THE SECOND VIGNETTE I WANT TO TALK TO YOU ABOUT IS TO UTILIZE MECHANISTIC METABOLIC AND GENE REGULATORY NETWORKS FOR MULTI-OMIC DATA INTEGRATION. THIS WAS, AGAIN, SUPPORTED BY AMP-AD AND WITH OUR WONDERFUL COLLABORATORS THAT I HAVE MENTIONED AS WE'VE GONE ALONG. AND IN PARTICULAR, JUST WANT TO ACKNOWLEDGE THE ALZHEIMER'S DISEASE METABOLOMICS CONSORTIUM, WHICH IS LED BY RIMA KADDURAH-DAOUK, WHICH REALLY DROVE A LOT OF WHAT I'LL SHOW HERE AROUND METABOLISM AND THE GENE REGULATORY NETWORK. WORK WAS DONE A LOT WITH CORY FUNK AT THE INSTITUTE FOR SYSTEMS BIOLOGY TAKING A BIG LEAD THERE, ALONG WITH OUR COLLABORATORS, NIL FER ERTEKIN-TANER AND TODD GOLDE.SO, I'M NOT GOING TO GO INTO THIS ONE IN DETAIL; YOU CAN READ ABOUT IT IN THE PAPER, OTHER THAN JUST TO SAY THAT WE DID AN INITIAL ANALYSIS WITH THE GENOME SCALE METABOLIC AND GENE REGULATORY NETWORKS AROUND BILE ACID USAGE IN THE BRAIN. IT TURNS OUT, THERE ARE QUITE SIGNIFICANT DIFFERENCES IN BILE ACIDS BETWEEN ALZHEIMER'S DISEASE PATIENTS AND NORMAL. THIS ONE DELVED INTO THE PATHWAYS THAT ARE BEHIND THAT. THERE'S THIS ALTERNATE PATHWAY THAT IS EXPRESSED; THE CLASSICAL FORMATION PATHWAY IS NOT. AND WITHOUT GETTING INTO THE DETAILS ON THIS, IT'S QUITE INTERESTING THAT WE DONÍT SEE ANY EVIDENCE FOR THE ENZYMES THAT ARE NECESSARY TO MAKE A LOT OF THE BILE ACIDS THAT ARE OBSERVED, SO WE EITHER HAVE ENZYMES THAT ARE PROMISCUOUS, SO THEY MAKE OTHER THINGS THAN WE ANNOTATE, OR THERE'S A MIS-ANNOTATION. OR AN ALTERNATE HYPOTHESIS IS THAT THESE BILE ACIDS ARE KNOWN TO BE MADE IN THE MICROBIOME, AND PERHAPS THEY ARE GETTING ACROSS THE BLOOD-BRAIN BARRIER. SO, BOTH OF THOSE IDEAS ARE VERY MUCH OPEN AND ARE BEING EXPLORED, AND ARE BEING EXPLORED IN MORE DETAIL IN THE JOINT GRANT THAT RIMA HAS WITH ROB KNIGHT WHERE THEYÍRE REALLY DIVING INTO THIS. AND YOUÍLL HEAR ABOUT THAT SOME OF THOSE EFFORTS LATER ON IN THE SUMMIT.BUT THE ONE IÍM GONG TO FOCUS ON PRIMARILY TODAYS IS NOT YET PUBLISHED, AND THIS IS AROUND SPHINGOLIPID METABOLISM IN ALZHEIMERÍS DISEASE. AND THEREÍS A BUNCH OF MOUNTING EVIDENCE THAT THIS IS AN IMPORTANT PATHWAY. SO, METABOLIC WIDE ASSOCIATION STUDIES HAVE FOUND ASSOCIATIONS WITH A NUMBER OF METABOLITES, SHOWN HERE. WE HAVE DONE WITH THE FLUX BALANCE ANALYSIS HAS SHOWN THAT THERE ARE DIFFERENCES IN THE CALCULATED FLUXES AT SOME OF THESE REACTIONS, SHOWN HERE. A NUMBER OF THE PROTEINS HAVE BEEN FOUND TO BE ALTERED THROUGH LOOKING AT MRIS, AND THERE ARE A NUMBER OF COMPOUNDS THAT CAN MANIPULATE THE METABOLISM IN THESE PATHWAYS. ONE OF WHICH THAT IÍLL FOCUS ON NOW, A FINGOLIMOD.SO, IF WE LOOK AT A MOUSE MODEL HERE, WEÍRE GOING TO LOOK AT AN APP/PS1 MOUSE, AND IT HAS TWO MAJOR DEFICIENCIES SHOWN HERE. ONE IS THAT IT HAS A DEFICIENCY IN BEING ABLE TO RECOGNIZE NOVEL OBJECTS -- THATÍS SHOWN HERE UNDER A. AND AT THE MECHANISTIC LEVEL, IT HAS ABNORMALLY LONG-TERM POTENTIATIONS, OR IT HAS LOW SYNAPSES. AND IF YOU GIVE IT FINGOLIMOD AND TARGETING THIS PATHWAY, WHAT YOU FIND IS THAT IT, IN FACT, RESTORES THE BEHAVIOR -- SO, THE MICE ARE THEN ARE ABLE TO RECOGNIZE OBJECTS, AND THEIR SYNAPSE FUNCTION JUST LIKE NORMAL. SO, THIS IS A REALLY INTERESTING RESCUE HERE OF THE APP/PS1 MOUSE. AND THIS IS FANTASTIC WORK ALL DONE MY HERMAN MORENO, SO ALL CREDIT TO HIM, BUT JUST ITS, I THINK, A REALLY INTERESTING PAPER THATÍS COMING OUT. AND PRIYANKA BALONI, FROM OUR GROUP, WHO ACTUALLY TOOK OVER THESE GRANTS FROM ME WHEN I MOVED TO ONEGEVITY, SHE -- THEY HAVE A BIG JOINT PAPER TOGETHER WITH ALL OF US THAT SHEÍS LEADING THAT INTEGRATES THE MODELING AND THE EXPERIMENTS, SO I THINK ITÍS A WONDERFUL STORY OF GOING QUITE A WAYS DOWN THE ROAD.SO, IN THE REMAINING TIME THAT I HAVE, I WANT TO TALK ABOUT SOME OF OUR MOST RECENT WORK, AND THIS IS DONE WITH A START-UP COMPANY CALLED EMBODYBIO THATÍS LED BY TOM PATTERSON, WHO HAS BEEN A LONG-TIME FRIEND AND COLLEAGUE FOR THE LAST 10 YEARS. AND HERE WHAT WEÍRE GOING TO BE LOOKING AT IS A HYBRID DYNAMIC AND BAYESIAN NETWORK MODEL OF BRAIN HOMEOSTASIS. AND THE IDEA HERE IS REALLY TO TRY AND MODEL WELLNESS TO UNDERSTAND DISEASE. BY MODELING HOMEOSTASIS, WHAT ARE ALL THE DIFFERENT MECHANISMS TO MAINTAIN THAT THAT WE KNOW ABOUT IN THE BRAIN, AND THEN SIMULATE PERTURBATIONS THERE FROM, AND TO DO IT IN A PERSONALIZED WAY. AND IÍM ACTUALLY REALLY EXCITED ABOUT THIS WORK.SO, ITÍS A SYSTEMS-PHYSIOLOGY STRATEGY, SO WE BUILD A MODEL AND ITÍS A HYBRID, AS I MENTIONED, BETWEEN BAYESIAN MACHINE LEARNING AND KINETIC MODELS. AND WHAT WE HAVE HERE ARE ALL THE DIFFERENT SUB-MODULES THAT YOU MIGHT EXPECT. SO, THERE'S DETAILS IN CHOLESTEROL AND LIPOPROTEIN PARTICLE METABOLISM, A AND PLAQUES, SYNAPTIC PLASTICITY AND COMPENSATION, MICROGLIA ACTIVITY, NEURO DEGENERATION AND TAU, NEURON ENERGY METABOLISM, AND IT PULLS DATA FROM ABOUT 452 PAPERS. SO, IT IS THE KIND OF THING THAT LEVERAGES ON SO MUCH AMAZING AND WONDERFUL WORK THAT"S BEEN DONE BY EXPERIMENTALISTS IN THE ALZHEIMERÍS FIELD FOR DECADES. AND WHAT WEÍRE DOING HERE IS AN ANALYSIS TO LOOK AT VARIABILITY IN MULTI-SYSTEM HOMEOSTASIS, AND WEÍRE GOING TO DO IT OVER DECADES-LONG TIME SCALE. SO, WE HAVE FAST EQUILIBRATING SYSTEMS HERE, AND WE HAVE SLOW TISSUE REMODELING. IT HAPPENS VERY SLOWLY OVER THE COURSE OF LIFE. AND SO, WHAT THIS LETS US DO IS WEÍVE SIMULATED NOW A DIGITAL POPULATION OF NEARLY TEN MILLION PEOPLE TO LOOK AT THE EFFECTS OF KNOWN VARIABILITY IN A BUNCH OF THESE PARAMETERS, AND WHAT THAT MEANS AS WE THINK ABOUT THE MANIFESTATION OF THIS DISEASE IN A POPULATION. SO, WEÍLL BE LOOKING AT A LOT OF THESE INDIVIDUAL PATIENT DIGITAL TWIN DATA.SO, WHATÍS VARYING HERE? SO, THE KIND OF THINGS THAT ARE VARYING -- SO APOE -- ARE YOU APOE2/4, ARE YOU 3/4, 4/4, ALL OF THOSE KIND OF THINGS GO IN. VARIATIONS IN OTHER GENES, LIKE APOA1, LDL RECEPTOR, AND SO FORTH, AND WE ALSO HAVE LOTS OF PARAMETERS ABOUT HOW THOSE THINGS EFFECT ASTROCYTE/NEURON/MICROGLIA, FOR EXAMPLE, CHOLESTEROL HOMEOSTASIS, AGAIN BUILDING ON A LOT OF EXPERIMENTAL WORK. WE'RE LOOKING AT VARIATIONS IN NEURON ENERGY METABOLISM, VARIATIONS IN MICROGLIA ACTIVATION, VARIATIONS IN SYNAPTIC COMPENSATION FOR NEURONAL LOSS, A LOT OF THINGS LIKE THAT THAT I DON'T HAVE TIME TO GET INTO ALL THE DETAILS. BUT WHAT I WANT TO SHOW YOU HERE, I THINK, IS QUITE INTERESTING. SO, IÍM GOING TO LOOK AT THIS: A PERCENT OF NEURONS IN NEGATIVE ENERGY BALANCE. SO, WHAT HAPPENS IS THEREÍS DATA THAT SHOWS THAT YOUR BASE METABOLIC CAPACITY GETS WORSE AS YOU AGE. YOUÍRE GOING TO SEE THAT AS THIS GREEN LINE THATÍS GOING TO COME DOWN. AND YOUR BASE METABOLIC LOAD GOES UP, AND WHATÍS SHOWN HERE ON THE X-AXIS IS BASICALLY A DIFFERENCE IN HOW HARD IT IS TO PROFUSE DIFFERENT TISSUES. SO, THIS IS JUST A FUNCTION OF THE GRAY MATTER PERCENTAGE. AND I'LL SHOW YOU THIS IN SIMULATION BECAUSE WHAT HAPPENS IS THAT IF THE CAPABILITY GOES BELOW THE NEED, WHAT WE'LL GET IS A CASCADE OF EVENTS THAT CAUSES SOME OF THESE NEURONS, STARTING WITH THE ONES THAT ARE HARDER TO PROFUSE. AND AS YOU GET CELL DEATH, THAT PUTS MORE AND MORE LOAD ONTO THE REMAINING CELLS IF YOU'RE GOING TO TRY TO MAINTAIN THE SAME COGNITIVE CAPACITY. AND SO, THIS IS JUST A SIMULATION OF THOSE TWO THINGS, AND HOW NEURON DEATH IS AFFECTED THROUGH THIS PROCESS OF NEGATIVE ENERGY BALANCE.NOW, ONE OF THE INTERESTING THINGS THAT COMES OUT OF THIS IS THAT APOE4, APOE 2, AND APOE3, THEY ALL HAVE EFFECTS ON -- THAT YOU CAN SIMULATE IN THE MODEL, ON THIS RAKE. AND IF ALL YOU DO IS LOOK AT THESE TWO PARAMETERS, I.E., HOW THE GOING AND CAUSING THIS NEGATIVE ENERGY BALANCE. IF ALL YOU'RE LOOKING AT IS THOSE TWO THINGS AND HOW APOE2, 3, AND 4 AFFECT THEM, WHAT YOU FIND IS THAT IS SUFFICIENT TO RECAPITULATE IN THESE MODELS, THE KAPLAN-MEIER CURVES, ASSOCIATED WITH ALL THE DIFFERENT GENETICS. SO, THAT SUGGESTS THAT THIS COULD BE A VERY MAJOR FACTOR IN WHAT'S GOING ON AROUND THOSE GENES THAT LEADS TO COGNITIVE DYSFUNCTION. THAT'S AGAIN AROUND UNDERSTANDING HOMEOSTASIS AND METABOLISM.SO, LET'S LOOK AT THE DYNAMICS FROM WHERE THAT COMES FROM. SO, WEÍRE ACTUALLY SIMULATING OVER TIME -- AND THIS IS JUST FOR APOE33 HERE. YOU CAN SEE TIME TICKING ACROSS AT THE TOP IN YEARS, AND WEÍRE JUST DOING A SIMULATION OF BOTH HOW MUCH A PLAQUE IS ACCUMULATING IN THIS CASE, AND COGNITIVE ABILITY. SO, THIS IS A PROJECTION OF A VERY HIGH DIMENSIONAL SPACE, BUT ON THESE TWO PARAMETERS.SO, IF WE THEN TAKE THOSE DYNAMICS AND WE FREEZE IT AT A POINT IN TIME. SO, LETÍS SAY THIS IS THE MOMENT AT WHICH WE GOT THE POST-MORTEM BRAIN SAMPLE. ALL RIGHT, SO WEÍRE FROZEN AT A MOMENT IN TIME, 75 YEARS OF AGE, AND WE CAN LOOK, AND WE WOULD COME UP WITH SOME OF THE CATEGORIES THAT WE ANALYZE, CERTAINLY, WITHIN AMP-AD, WHICH IS THE GROUP THAT IÍVE BEEN MOST ASSOCIATED WITH, BUT IÍM SURE ACROSS OTHER GROUPS, AS WELL. SO, HERE WE HAVE OUR CONTROL IN GREEN. WE HAVE OUR TYPICAL ALZHEIMERÍS WHERE YOU GOT A PLAQUES AND COGNITIVE DECLINE. WE HAVE THE EMERGENCE, JUST BY LOOKING AT VARIABILITY, THE NECESSARY EMERGENCE OF THE PATH AGING SUBGROUP. AND FOR THOSE WHO ARENÍT FAMILIAR WITH THAT TERMINOLOGY, PATH AGING WE USE AS A TERM TO REFER TO PEOPLE THAT HAVE AMYLOID IN THEIR BRAIN, BUT NOT COGNITIVE DECLINE. AND THEN, THEREÍS ALSO THE GROUP DOWN HERE WHERE YOU END UP WITH INDIVIDUALS THAT WE WOULD PREDICT HAVE COGNITIVE DECLINE, BUT NOT AMYLOIDS. SO, THIS WOULD BE NON-AMYLOID ASSOCIATED DEMENTIAS, COULD BE TAUOPATHIES, OR SOMETHING LIKE THAT.AND SO, THESE SNAPSHOTS IN TIME, THEN -- AND WE CAN DO THEM -- HERE IÍM SHOWING THEM FOR APOE34, 33S, AND 23S SO WE CAN LOOK AT DIFFERENT VARIATIONS. AND AS I SAID, YOU GET THIS PREDICTION FOR THIS EMERGENCE OF PATH AGING, AND IT SHOWS THAT THAT COMES IN TO BE LOWER THAN WITH ALZHEIMERÍS, AS WOULD BE SHOWN HERE. AND IF YOU COMPARE THAT TO DATA, THATÍS QUALITATIVELY WHAT WE SEE. SO, IT MAKES THIS PREDICTION OF THIS EMERGING PHENOTYPE OUT OF THE SIMULATIONS THAT SAYS, ñLOOK, IF YOU JUST LOOK AT VARIABILITY ACROSS THE POPULATION, YOU WOULD EXPECT AS A FUNCTION OF THE PROCESSES, THAT YOU WOULD SEE PATH AGING. AND, IN FACT, YOU DO.SO, HERE, THIS IS NOT A SIMULATION; THIS IS JUST LOOKING AT DATA FROM AMP-AD. BUT ONE OF THE THINGS WE HAVE TO THINK ABOUT IS THE DISTRIBUTION OF THE PHENOTYPES BASED ON AGE OF DEATH BECAUSE THEY HAVE DIFFERENT KAPLAN-MEIER CURVES. PEOPLE WITH APOE4 ARE GOING TO DIE EARLIER, SO THERE'S THESE BIASES IN THE DATA. THE AVERAGE AGE OF DEATH ON THE POST-MORTEM SAMPLES WE HAVE IS 86 YEARS OLD. AND SO, IF WE DIVE, THEN, INTO THIS, WE CAN SEE HOW THESE MODELS ALLOW US TO GO FROM A SNAPSHOT TO A DYNAMIC SIMULATION. SO, HERE WHAT WE DID IS WE LOOKED AT ALL THE PATH AGING SET THAT WERE, IN THIS CASE, APOE34, AND WE SIMULATED HOW THEY STAYED ALIVE. WHEN DO WE THINK THEY WOULD HAVE GOTTEN ALZHEIMER'S? NOW, SO WE DO THAT SIMULATION, AND IT TURNS OUT THAT IF WE SIMULATE FOR THE APOE34S, WE THINK THAT 23 PERCENT OF THEM WOULD NOT HAVE GOTTEN ALZHEIMER'S BY THE TIME THEY WERE 100; THATÍS WHATOS SIMULATED. SO, THEREÍS A VERY BIG DIFFERENCE BETWEEN THE PATH AGING SET AND THOSE THAT, IN FACT, GOT ALZHEIMERÍS DISEASE. AND SO, WHAT WAS SPECIAL ABOUT THESE INDIVIDUALS? AND THE THINGS THAT JUMP OUT FROM THIS IS THAT THE INDIVIDUALS WHO WERE PATH AGING IN THE APOE34, THEY HAD PARTICULARLY HIGH CEREBRAL PROFUSION, THEY HAVE PARTICULARLY EFFICIENT NEURON METABOLISM, THEY HAVE HIGH APOA1 AUGMENTATION OF APOE CHOLESTEROL TRAFFICKING CAPACITY, AND THEY HAVE PARTICULARLY HIGH RESILIENCE TO CHOLESTEROL DYSHOMEOSTASIS. SO, THEYÍRE ABLE TO MEDIATE NEURON METABOLIC STRESS BETTER. NOW, IF WE LOOK AT THE APOE33S IN THE PATH AGING SET -- AGAIN, THIS IS LOOKING AT AMP-AD DATA. HERE WE ACTUALLY PREDICT THAT ONLY SIX PERCENT OF THEM WOULD NOT HAVE ALZHEIMERÍS DISEASE BY THE TIME THEY HIT AGE 100. IN FACT, WE PREDICT THAT ALMOST -- FOR MOST OF THESE INDIVIDUALS, WE PREDICT THAT THEYÍRE ONLY A FEW YEARS AWAY FROM ALZHEIMERÍS ONSET. SO, IT SUGGESTS THAT THE DIFFERENCE BETWEEN LOOKING AT THE PATH AGING FOR APOE33 IS VERY DIFFERENT THAN LOOKING AT THE SET FOR APOE34, AND THAT THE APOE34 ARE LIKELY TO BE INFORMATIVE BECAUSE THEREÍS A MUCH MORE SUBSTANTIAL DIFFERENCE BETWEEN THEM AND THE ALZHEIMERÍS SET THAN WE HAVE WITH THE APOE33S.OKAY. SO, HOW CAN THESE MODELING APPROACHES BE USEFUL FOR ALZHEIMERÍS DISEASE? SO, FIRST, WE CAN IDENTIFY BY SIMULATION A SUBSET OF PATIENTS WHO MIGHT BENEFIT FROM A GIVEN DRUG OR COMBINATION OF DRUGS. AND THIS INCLUDES GOING BACK AND LOOKING AT PREVIOUSLY DEVELOPED ANTI-AMYLOID THERAPIES THAT MIGHT HAVE -- MIGHT MAKE A DIFFERENCE IN A SUBSET OF PATIENTS, OR IN COMBINATION WITH SOMETHING, WHERE WE CAN SIMULATE ALL OF THOSE THINGS ON THIS KIND OF A MODELING FRAMEWORK. A SECOND, WE CAN GO FROM SNAPSHOTS TO PREDICTED DYNAMICS, AND I SHOWED THAT WHERE YOU CAN TAKE A SNAPSHOT AND PREDICT SOMETHING ABOUT WHATÍS GOING ON IN THAT PROCESS BEFORE AND AFTER BY GOING BACK TO FIRST PRINCIPLES AND THE VARIABLES THAT YOU CAN MEASURE OUT OF AN INDIVIDUAL, A LOT OF WHICH IS ACTUALLY TIED BACK TO GENETICS. AND THAT LETS US SELECT THE MOST RELEVANT SUBPOPULATIONS TO FOCUS ON. THIRD -- AND THIS IS MAYBE THE ASPECT IÍM MOST EXCITED ABOUT, IS THAT WHEN YOU DO THESE SIMULATIONS, IT SHOWS THAT ONCE SOMEONE WE PREDICT THAT WHEN SOMEONE HAS A MOCA SCORE, SAY, OF 29; THEYÍRE JUST STARTING TO SHOW COGNITIVE DECLINE. THEYÍRE ABOUT 20 PERCENT DOWN THIS S-CURVE WHERE YOUÍRE GETTING THE CASCADE OF NEURON DEATH. SO, WHAT WE REALLY WANT IS DEVELOP BIOMARKERS TO WHERE YOUÍRE AT WHEN YOUÍRE APPROACHING THAT CLIFF, AND THEN INTERVENTIONS TO BACK YOU AWAY FROM THE CLIFF BECAUSE IÍM REALLY CONVINCED ONCE YOU START GOING DOWN AND YOUR NEURONS ARE GOING DOWN THAT CASCADE OF DEATH, THATÍS REALLY HARD TO IMAGINE HOW WEÍRE GOING TO PUT THAT BACK TOGETHER, AT LEAST WITHOUT GETTING TOO SCI-FI. BUT WE CAN DO A LOT TO STOP THAT FROM HAPPENING, AND THAT, I THINK, WEÍVE REALLY GOT TO PUT A TON OF OUR FOCUS THERE.SO, WE CAN DEVELOP THERAPIES AIMED AT INCREASING RESILIENCE TO ALZHEIMERÍS DISEASE. HOW DO YOU BECOME ONE OF THOSE PEOPLE IN THE PATH AGING SET? HOW DO WE PUSH PEOPLE IN PATH AGING EVEN FURTHER THAT WAY SO THAT WE ARE MORE RESILIENT AS A POPULATION TO ALZHEIMERÍS DISEASE? WE CAN USE THIS DESIGN OF BIODIGITAL TWINS TO SIMULATE CANDIDATE THERAPEUTICS. AND IN FACT, WE HAVE A BIG -- ANYWAY, BIG EFFORTS GOING ON IN THIS, BUT WE CAN SIMULATE CANDIDATE THERAPEUTICS AGAINST INDIVIDUALS IN POPULATIONS, AND WE CAN DESIGN PERSONALIZED COMBINATION THERAPIES. SO, THEREÍS A LOT OF USES, I THINK, FOR THIS KIND OF A MODELING APPROACH WITHIN THE CONTEXT OF WHAT WE CARE ABOUT IN ALZHEIMERÍS DISEASE. SO, TO SUMMARIZE, THEN, THE WHOLE TALK HERE, HIGHLY SIGNIFICANT PROGRESS HAS BEEN MADE ON GENERATING LARGE-SCALE DATA ON ALZHEIMERÍS DISEASE; ITOS A CREDIT TO THE MANY WONDERFUL PEOPLE WHO ARE INVOLVED HERE IN THE SUMMIT AT THE NIH, AT THE NIA, TO THE LEADERSHIP, TO CONGRESS STEPPING UP AND PUTTING MONEY INTO THIS AREA, SO WE HAVE A LONG WAY TO GO, BUT WEÍVE MADE A LOT OF PROGRESS. MODELS THAT ARE PURELY DATA-DRIVEN, AS WELL AS THOSE THAT GO INTO THE DATA WITH VERY FOCUSED MECHANISTIC HYPOTHESES CAN REALLY HELP US DRIVE DISCOVERY, AND I THINK BOTH OF THOSE ARE REALLY IMPORTANT. METABOLIC INTERVENTIONS, AS WE SHOWED, CAN BE MODELED, AND WE DO HAVE EXPERIMENTAL CONFIRMATION OF RESTORED COGNITIVE ABILITY, AT LEAST IN THE MOUSE MODEL. MICE ARE EASIER THAN HUMANS, BUT I THINK THATÍS REALLY AN IMPORTANT STEP, IN TERMS OF SHOWING THAT THESE METABOLIC INTERVENTIONS CAN HAVE AN EFFECT. ITÍS ABSOLUTELY CRITICAL, AS I SPENT A LOT OF THE LAST PART OF THE TALK ON, TO MOVE FROM SNAPSHOTS TO DYNAMICS, AND THESE MECHANISTIC MODELS OF DISEASE TO DELVE INTO COMPLEXITY, INCLUDING THESE BIODIGITAL TWINS FOR INDIVIDUAL PATIENTS. ITÍS REALLY ESSENTIAL -- THIS IS KIND OF MY WHOLE THING, TO UNDERSTAND WELLNESS, TO UNDERSTAND HOMEOSTASIS, TO MODEL THAT AS WELL AS WE POSSIBLY CAN SO THAT WE CAN GET INTO WHAT IS DRIVING THE BREAKDOWN OF THOSE SYSTEMS, AND TO DO SO IN THE CONTEXT OF AGING AND MECHANISTIC NETWORKS. I THINK THATÍS REALLY KEY TO THE FUTURE. AND OBVIOUSLY, THE FOCUS ON PATIENTS AND HOW WE CAN MOVE AS FAST AS POSSIBLE TO HELP THEM IS OUR MOST IMPORTANT GOAL AS A COMMUNITY. WITH THAT, I JUST WANT TO THANK THE ORGANIZERS, AGAIN, FOR GIVING ME THE OPPORTUNITY TO SPEAK TO YOU TODAY. I WANT TO THANK ALL OF THE WONDERFUL COLLABORATORS IÍVE HAD AT THE NIH OVER THE LAST SEVERAL YEARS. I WANT TO THANK ALL THE FUNDING THATÍS GONE INTO ALL THESE AMAZING EFFORTS. MY WONDERFUL LAB AT ISB, MOST NOTABLY, CORY FUNK, WHOÍS BEEN A TERRIFIC PARTNER IN ALL THINGS ALZHEIMERÍS, AND PRIYANKA BALONI, WHOÍS DRIVEN SO MUCH OF WHAT WEÍVE DONE ON THE METABOLIC SIDE. I THINK I THANKED EVERYONE AS I WENT ALONG. IF YOUÍRE INTERESTED IN ANY OF THIS, MANY OF YOU KNOW ME; FEEL FREE TO REACH OUT TO ME PERSONALLY, OR ALSO, YOU CAN REACH US -- ESPECIALLY ON THE LAST PART, AT INQURIES@ONEGEVITY.COM, THAT WILL GO TO ME AND THE TEAM, AND YOU CAN REACH ME THERE, AS WELL. SO, THANK YOU, EVERYONE, AND LETÍS HAVE A WONDERFUL SUMMIT WELL, THANK YOU. FOR KICKING OFF THE SUMMIT. WE'LL HAVE A SHORT BREAK AND FOLLOWING AFTER THE BREAK WE'LL HAVE SESSION ONE ON DE CONSTRUCTING DISEASE COMPLEXITY. PLEASE STAY TUNED AND WE'LL BE BACK IN A FEW MINUTES. THANK YOU. >> WELCOME TO SESSION ONE, DE CONSTRUCTING DISEASE COMPLEXES FROM SINGLE CELLS AND FROM DISEASE TO MULTI-SCALED MODELS. I'M CATHERINE KACZOROWSKI AND WITH DAVID BENNETT FROM RUSH UNIVERSITY AND THANK YOU FOR ATTENDING AND PLEASE SUBMIT QUESTIONS TO THE CHAT BUT WE'RE GOING TO BE ABLE TO DISCUSSION AS A PANEL AFTER THE LIGHTNING ROUND TODAY. WITH THAT, DAVID, TAKE IT AWAY. >> THANK YOU, CATHERINE. THANK YOU, TO THE ORGANIZATIONERS FOR GIVING ME -- ORGANIZERS FOR GIVING ME A CHANCE TO SPEAK AND FOR THE SPEAKERS THROUGHOUT THE SUMMIT AND THE NIA LEADERS FOR THEIR EFFORT. THERE'S SOME SLIDES. SO SESSION ONE DE CONSTRUCTING DISEASE COMPLEXITY AND I'LL TALK A LITTLE BIT ABOUT DISEASE COMPLEXITY USING DATA FROM STUDIES AND THE RUSH PROJECT LISA DESCRIBED IN THE FIRST PLENARY SESSION. ON THE LEFT, WHAT YOU SEE IS A RANDOM SAMPLE OF COGNITIVE FUNCTION, 0 ON THE RIGHT IS TIME OF DEATH MINUS, 10-20-25 PRIOR TO TOGETHER AND SPECIFIC TRAJECTORIES OF PEOPLE WOULD CAME TO AUTOPSY. ON THE RIGHT WE SEE A LINEAR MIX MODE OF THE SAME PEOPLE I AND THE SOLID BLACK LINE ARE RATE OF YEARS AND YOU SEE SOME DECLINING FASTER AND SMALLER AND SOME DECLINING NOT AT ALL. WHAT WE WANT TO UNDERSTAND IN COGNITIVE AGEING IS WHAT CONTRIBUTES TO THIS HETEROGENEITY OF COGNITIVE TRAJECTORIES AND THEN OF COURSE HOW TO USE THAT INFORMATION TO INTERVENE ON COGNITIVE DECLINE. SO HERE'S A LOOK AT BRAIN PATHOLOGIES. WE SEE A BLACK LINE THE REFERENCE GROUP OF MYTHICAL PEOPLE WITH NO PATHOLOGY. THERE'S NOBODY WITH NO PATHOLOGY. THESE ARE PEOPLE WHO DON'T HAVE PA PATHOLOGIC AD AND DON'T HAVE THE OTHER BRAIN PATHOLOGIES. THE SECOND LINE, THE RED LINE IS ALZHEIMER'S DISEASE PATH OWE LOGICALLY. THE GREEN LINE YOU SEE DECLINING FASTER ARE OTHER COMMON NEURODEGENERATIVE DISEASE PATHOLOGIES AND TDP53 AND YOU SEE OTHER DISEASE AND ARTERIOSCLEROSIS. IF WE ASK HOW MUCH OF THE PERSON-SPECIFIC TRAJECTORIES DO ALL THESE PATHOLOGIES ACCOUNT FOR WHAT WE SEE IN THE PIE CHART ON THE BOTTOM RIGHT IS THEY ACCOUNT FOR LESS THAN HALF OF THE PERSON-SPECIFIC DIFFERENCES IN THESE TRAJECTORIES. SO I'M NOT SAYING THESE DISEASES DON'T ACCOUNT FOR MORE, BUT WE'RE SIMPLY SAYING IS THE PATHOLOGIC DISEASES ACCOUNT FOR 43%. THE NEXT QUESTION WE HAVE IS GIVEN ALL THE DIFFERENT BRAIN PATHOLOGIES HOW MANY COMBINATIONS DO WE SEE? IT TURNS OUT THERE ARE ALMOST 250 COMBINATIONS AND OVER 1,000 BRAINS. PATHOLOGIC AD IS PRESENT THAN 6% OF THE SAMPLE. NO PATHOLOGY IS THE MYTHICAL A LITTLE BIT OF AD BUT NOT ENOUGH TO MEET PATHOLOGIC CRITERIA AND AD WITH CAA AND AD, TDP, ETCETERA AND ON THE BOTTOM RIGHT YOU SEE A LONG TAIL OF ALMOST 100 PEOPLE WITH ONE PERSON WITH A SPECIFIC COMBINATION OF BRAIN PATHOLOGIES. THIS IS THE DAUNTING TASK OF WHAT WE'RE TRYING TO UNDERSTAND. AND ONE APPROACH TO DO THIS IS TO DEVELOP A BIOMARKER FOR EACH OF THE PATHOLOGIES MEANT TO DEVELOP A COCKTAIL FOR EACH ONE. YOU REALIZE THAT PEOPLE DON'T WANT TO GET DEMENTED AND BE TREATED AND THEY WANT TO NOT BE DEMENTED AND LOOK AT BIOMARKERS AND DOING COCKTAILS AT PEOPLE AT RISK OF ALZHEIMER'S DISEASE IN THE U.S. OVER 100 MILLION PEOPLE AND THAT SEEMS DAUNTING. IF THERE'S ANOTHER WAY TO SIMPLIFY THIS AND I'LL PICK UP ON THEMES RAISED IN THE PLENARY. SO CAN WE GO AFTER COMPLEXITY? IN THIS CASE AND WE GO AFTER RESILIENCE AND WE SEE RNA SEQ CO-EXPRESSION AND THIS IS CONTINUAL PROBABILITY MODEL AND SEE COGNITIVE DECLINE ON THE BOTTOM AND THIS MODULE. MODULE 109 THAT GOES DIRECTLY TO COGNITIVE DECLINE BYPASSING AMYLOID AND TAU AND THERE'S A THICK LINE STRAIGHT TO COGNITIVE DECLINE. IT BYPASSES ALL THE OTHER PATHOLOGIES. THIS IS A MOLECULAR NETWORK OF 390 GENES ASSOCIATED WITH RESILIENCE. WE CAN TREAT RESILIENCE AND IMPROVE RESILIENCE OR OFFSET THE EFFECTS OF ANY PATHOLOGY OR ANY COMBINATIONS OF PATHOLOGIES. NEXT SLIDE. SO WE CAN LOOK INSIDE THE NETWORK AND IDENTIFIED A NUMBER OF GENES AND CAN GET TARGETED PROTEOMICS TO MEASURE THE PROTEINS AND WHAT WE SEE ARE TWO PROTEINS. IS THIS CASE THE TWO I SELECTED ARE NOT THE MOST AND THESE ARE TWO PROTEINS HIGHLY SIGNIFICANT AND UNRELATED TO ANY BRAIN PATHOLOGY. BECAUSE WE MODEL RESILIENCE AS THE RESIDUAL OF COGNITIVE DECLINE AFTER CONTROLLING FOR BRAIN PATHOLOGIES WE FIND PROTEINS ASSOCIATED WITH MORE OR LESS RESILIENCE. WE SEE COGNITIVE DECLINE CONTROLLING FOR DEMOGRAPHICS OF PATHOLOGIES AND AK4 ASSOCIATED WITH LESS RESILIENCE AND YOU SEE KINASES AND DRUGGABLE AND YOU TRY TO PUSH THESE IN OPPOSITE DIRECTIONS WE CAN ALSO DO UNTARGETED WORK AND DO PROTEOME WIDE ASSOCIATION STUDIES THROUGH RESILIENCE AND IDENTIFY EIGHT ADDITIONAL PROTEINS ASSOCIATED WITH RESILL YENS. -- RESILIENCE. I CALL THIS THE CHICAGO PLOT BECAUSE THE P VALUES THAT GO UP ARE POSITIVELY ASSOCIATED AND THE ONES THAT GO DOWN ARE NEGATIVELY ASSOCIATED IF YOU LOOK AT THE CHICAGO SKYLINE AT NIGHT YOU'LL SEE THE REFLECTION OF ALL THE BUILDINGS. FINALLY, TO ACTUALLY UNDERSTAND HOW THE PROTEINS WORK WE'LL HAVE TO MODEL THEM. ONE WAY TO THINK ABOUT THIS IS MODELLING THEM IN AN ICSC BECAUSE WE CAN GET THEM IN LIVING PERSON. THERE WE ARE JUST TAKING ADVANTAGE OF THE GENOMIC DIVERSITY BETWEEN PEOPLE. ON THE TOP LEFT I'M SHOWING A POLYGENIC RISK SCORE FOR RESILIENCE WHERE WE ACCOUNT FOR ABOUT 20% OF RESILIENCE THROUGH A POLY GENIC RISK SCORE AND MAY HAVE ENOUGH PERSON-SPECIFIC DIFFERENCES IN THE GENOMIC RISK TO BE ABLE TO MODEL RESILIENCE IN A DISH. HOW DO WE DO THAT? ONE WAY IS TO LOOK AT MOLECULAR NETWORKS. FOR EXAMPLE, IN MODULE 109, WE CAPITULATE IT IN A DISH OF IPSC. ONE CAN DO EXPERIMENTS EITHER CRISPR OR DUAL COMPOUNDS TO TRY TO UNDERSTAND HOW TO MANIPULATE PROTEINS IN ADDITION TO EFFECT MODULE 109. THERE'S A NUMBER OF WAYS TO THINK OF MODELLING STRESS AND RESILIENCE IN A DISH. AND ASSOCIATING THAT WITHIN PEOPLE AND RESILIENCE. MODULE 109 IN THE DISH IS CORRELATED WITH MODULE 109 FROM THE ACTUAL BRAIN NETWORKS. WE SEE LOSS OF COGNITION OF AGE AS A COMPLEX FUNCTION OF MULTIPLE BRAIN PATHOLOGIES INTERACTING WITH RESILIENCE MARKERS, NUMEROUS GENOMIC, PSYCHOLOGICAL RISK FACTORS ARE ASSOCIATED WITH COGNITIVE DECLINE AND NOT ASSOCIATED WITH BRAIN PATHOLOGY AND LISA TALKED ABOUT A LOT OF THOSE RISK FACTORS. THERE'S NO REVOLUTIONARY FACTOR TO COMBAT EACH PATHOLOGY AND ELIMINATING ANY INDIVIDUAL PATHOLOGY WILL ONLY PREVENT A SMALL INVARIABLE PORTION OF DISEASE. IT MAY NOT BE PRACTICAL OR EFFECTIVE TO DEVELOP DRUG COCKTAILS TO TARGET EACH ONE. WE CAN USE MULTI-LEVEL OMICS DATA TO DISCOVER NEW GENES AND PROTEINS INVOLVED IN COGNITIVE AGING AND THESE ARE ASSOCIATED WITH RESILIENCE CAN BE A RICH SOURCE OF THERAPEUTIC TARGET TO DETECT THE BRAIN FOR PATHOLOGIES. WE CAN FIND SOME OF THESE IN THE AMP AD PORTAL. I WANT TO THANK EVERYONE AGAIN. WE HAVE DATA YOU CAN FIND AT THE AD KNOWLEDGE PORTAL AND AVAILABLE FOR THE COMMUNITY FOR SHARING SO YOU CAN TEST YOUR OWN IDEAS AS WELL. NOW, I'M GOING TO TURN IT BACK TO CATHERINE WHO WILL TAKE SOME OF THESE IDEAS AND TRANSLATE THEM INTO PRE-CLINICAL MODELS. THANK YOU VERY MUCH. CATHERINE. >> THANK YOU, DAVID. IT'S A PRIVILEGE TO BE INVITED TO CO-CHAIR THIS AMAZING SESSION WITH YOU. AS YOU WELL KNOW, THE WORK I'M GOING TO TALK ABOUT BRIEFLY TODAY HAS BEEN INFLUENCED BY MANY YEARS OF HIGHLY NEITHERED DEBATES WITH OUR COLLEAGUES AT ROSMAP AND RESILIENCE TO ADD MEETINGS AND IN RESPONSE TO THE GAPS AND OPPORTUNITIES IDENTIFIED BY PRIOR AD RESEARCH SUMMITS. WHAT'S FOLLOWED IS OUR RIGOROUS EXPERIMENTAL TEST OF THE UTILITY OF DIVERSE MOUSE POPULATIONS WE THINK BETTER MODEL A GENETIC AND PHENOTYPIC COMPLEXITY OF HUMANS FOR DISCOVERY OF RESILIENCE TARGETS FOR AD. WE'VE GONE FROM DISCOVERY IN A MOUSE TO TRANSLATIONAL CHECKS IN HUMAN AND THEN BACK INTO THE MOUSE FOR MECHANISTIC STUDIES. IN PARALLEL, WE'VE BEEN USING INFORMATION GLEANED FROM HUMAN GENETIC STUDIES TO DESIGN AND CRITICALLY EVALUATE THE FIRST ALZHEIMER'S DISEASE REFERENCE PANEL WITH MICE WE HAVE DESIGNED TO ENABLE EXPERIMENTATION AND REFINEMENT OF PRECISION MEDICINE APPROACHES FOR AD. SO I THINK WE CAN ALL AGREE NO MODEL OF HUMAN AD IS PERFECT BUT I HOP WE DON'T TAKE AWAY -- HOPE WE DON'T TAKE AWAY AND WE'VE SEEN A TREMENDOUS AMOUNT OF DEVELOPMENT IN MOUSE MODEL BETTER ALIGNED TO THE HUMAN CONDITION BY INCORPORATING GENETIC DIVERSITY. THAT'S IN LARGE PART BECAUSE ALZHEIMER'S IS A POLYGENETIC DISEASE. THINK OF THE MODEL NOT AS A SINGLE GENOTYPE OR STRAIN OF MOUSE BUT RATHER A POPULATION WHERE INDIVIDUALS FALL ON A CONTINUUM FROM HIGH TO LOW RISK. SINCE DAVID POINTED OUT, AGING IS THE GREATEST RISK FACTOR FOR DEMENTIA AND A SIGNIFICANT PORTION OF PERSON-SPECIFIC DIFFERENCES IN COGNITIVE LOSS ARE NOT EXPLAINED BY NEUROPATHOLOGIES AND WE SET OUT TO IDENTIFY GENES ASSOCIATED WITH NORMAL, NON-PATHO LOGICAL AGING AND EVALUATE THEIR TRANSLATIONAL RELEVANCE USING A WEALTH OF HUMAN DATA MADE AVAILABLE THROUGH THE ALZHEIMER'S GENETICS CONSORTIUM, ROSMAP AND THE AMP AD PORTAL AN OPEN PLATFORM PIONEERED BY THE NIA LEADERSHIP TO CENTRALIZE AND SHARE DATA RELEVANT TO AD. SO IN THIS PAPER WE PERFORMED MEMORY TESTS IN NEARLY 500 AGING MICE FOLLOWED BY GENETIC MAPPING AND THE PROTEIN WAS ASSOCIATED WITH INDIVIDUAL DIFFERENCES IN MEMORY DECLINE. IN COLLABORATION WITH OTHERS WE CROSS-CHECKED OUR DISCOVERY AGAINST HUMAN GENETIC AND OMICS DATA FROM PORT-MORTEM TISSUE AND FOUND A SIGNIFICANT ASSOCIATION WITH AD ACROSS MULTIPLE SCALES, DNA, RNA AND PROTEIN THAT TOGETHER ASSOCIATE THE IDEA THAT DL GAP TWO IS A RESILIENCE FACTOR AND LOOKED WHERE A MECHANISM WHERE IT CAN PROMOTE RESILIENCE AND RESILIENT MICE HAD DENDRITIC PROFILES REPORTED IN AD RESILIENCE CASES BY THE LAB IN YEARS PRIOR. THUS, STUDIES OF NON-PATHOLOGICAL COGNITIVE AGING IN MICE HAVE REAL POTENTIAL FOR NOMINATING NEW HUMAN RELEVANT AD TARGETS AND PROVIDE A SYSTEM TO CONDUCT VIGOROUS CAUSAL TESTS THROUGH GENOME EDITING AND TO SCREEN INTERVENTIONS IN A WAY THAT CAN'T BE DONE IN HUMANS. WE'VE ALSO RECENTLY SHOWN INCORPORATING DENETIC DIVERSITY OF -- GENETIC DIVERSITY IN MOUSE MODELS INCREASES THE POTENTIAL. AND IN THE MODEL WE COMBINED A WELL ESTABLISHED MOUSE MODEL OF ALZHEIMER'S DISEASE AND TRANS-GENIC LINE WITH A GENETICALLY DIVERSE REFERENCE PANEL FOR 28 STRAINS OF REPRODUCIBLE MICE THAT HARBOR IDENTICAL HIGH-RISK HUMAN MUTATIONS BUT VARY ACROSS THE REMAINDER OF THEIR GENOME AND THE GLUTAMATES THAT SERVE AS NON-PATHOLOGICAL CONTROLS. AFTER THE GENERATION WE FULLY CHARACTERIZED THE MICE. WE MEASURED THEIR WORKING MEMORY LONGITUDINALLY AND AT 6 AND 14 MONTHS THEY WENT THROUGH MORE DETAILED PHENOTYPE TYPE LINE WITH ACQUISITION AND MEMORY TESTING FOLLOWED BY HARVEST AND TISSUE BIOBANKING. NOTABLY, THIS VARIATION AND THE AGE OF ONSET OF MEMORY DEFICITS SHOWN ACROSS OUR STRAINS LOOKS A LOT LIKE VARIATION THAT IS SEEN IN HUMAN PATIENTS WITH THESE MUTATIONS ON THE RIGHT. IN ADDITION, WE'VE ALSO SHOWN THIS PANEL EXHIBITS HIGH DEGREES OF GENETIC OVERLAP WITH HUMAN AD STARTING WITH THE HIGHEST RISK PART FOR SPORADIC ALZHEIMER'S DISEASE WE FOUND A SIGNIFICANT AFFECT OF HPOE AND WERE ABLE TO VALIDATE THIS BY INTRODUCING THE SINGLE APOE VARIANT USING CRISPR AND COMPUTED A POLY GENETIC RISK SCORE FOR EACH STRAIN FROM KNOWN HUMAN AD RISK LOCI AND FOUND THE GENETIC RISK SCORE WAS SIGNIFICANTLY ASSOCIATED AND PREDICTIVE OF OUTCOMES IN THE MOUSE STRAINS AND WE CREATED A MODEL OF AD WHERE DIFFERENT COMBINATIONS OF RISK AND RESILIENCE GENE VARIANTS IMPACT COGNITIVE DECLINE. NEXT, WE WANTED TO KNOW HOW GENE EXPRESSION PROFILES FROM INDIVIDUAL STRAINS ALIGNED WITH HUMAN AD PROFILES WHICH RECENTLY WERE SEPARATED INTO FIVE DIFFERENT SUBTYPES BY A GROUP. USING RNA SEQUENCING GROUP FROM THE HIPPOCAMPUS WE APPLIED A SUPERVISED CLUSTERING APPROACH AND FOUND DIFFERENCES IN THE CLUSTERS. AND WE'RE EVALUATING HOW SEX AND DIET MAY INFLUENCE THE PROFILES IN A LARGE COHORT OF THESE STRAINS. COLLABORATIVE WORK HAVE RECENTLY SHOWN HOW TRANSCRIPTIONAL SIGNATURES USING AN ALGORITHM REVEALS HIGH ALIGNMENT FOR EACH CELL TYPE WITH ASTROCYTES SHOWING THE HIGH EST DEGREE OF ALIGNMENT BETWEEN MOUSE AND HUMAN XDs. YOU CAN LEARN MORE ON HER TALK AT THE LINK BELOW. NOW THAT WE DEVELOPED AND VALIDATED THE AD BXDs FOR MODELLING THE COMPLEX HETEROGENEITY OF HUMAN AD, MY LAST SLIDE SHOWS THE CURRENT AND FUTURE WORK BEING PURSUED THROUGH COLLABORATIONS WITH MANY COLLEAGUES FOR WHOM I'M INCREDIBLY GRATEFUL TO WORK WITH. IN ADDITION TO ALIGNING OUR STRAINS TO THE SUB TYPES WE'RE GENERATING MIXED PATHOLOGY MODELS MAINTAINED ON A GENETICALLY DIVERSE BACKGROUND IN ORDER FOR US TO CHARACTERIZE THEM USING OUR CROSS-SPECIES APPROACH. OUR GOAL IS TO DEFINE MODELS OF SUSCEPTIBILITY TO TEST-RESILIENCE BASED INTERVENTIONS WE DEVELOPED AND VALIDATED THE AD BXDs AS A TRANSLATIONAL MODEL, MY LAST SLIDE ILLUSTRATES THE CURRENT AND FUTURE WORK WITH SO MANY COLLEAGUES HERE TODAY FOR WHOM I'M GRATEFUL TO WORK WITH. SO IN ADDITION ON THE TOP LEFT, IN ADDITION TO THE STRAINS TO HUMAN AD SUB TYPES WE ARE GENERATING MIXED MODELS MAINTAINED ON A GENETICALLY DIVERSE BACKGROUND TO CHARACTERIZE THESE USING OUR CROSS-SPECIES APPROACH TO TEST RESILIENCE INTERVENTIONS AND TEST HOW THEY WORK WITH THE MODEL AD CONSORTIUM. ON THE TOP RIGHT WE'LL CONTINUE TO INTEGRATE PHENOTYPE DATA AND WORKING TOWARDS POLYGENETIC RISK SCORES IN MICE ALIGNED TO GWAS PSYCH TRAITS IN PART OF THE PSYCH AD CONSORTIUM. ASSAYS SENSITIVE TO GENETIC RISK SCORES FOR PSYCHIATRIC AND OTHER TRAITS WILL BE POWERFUL RESOURCES FOR CLINICAL EVALUATION OF INTERVENTIONS. THE RICH CLINICAL AND BEHAVIORAL TRAIT DATA FROM PSYCH AD ARE BEING INTEGRATED WITH BRAIN IMAGING AND OMICS AND SINGLE-CELL DATA TO IDENTIFY TITERS OF RESILIENCE TO NEURAL AND PSYCHIATRIC CONDITIONS AND DESIGNING IN VITRO 3-D MODELS OF MOUSE AD SUB TYPES TO TEST NEW RESILIENCE TARGETS IDENTIFIED THROUGH CAUSAL INFERENCE ANALYSES AND THOSE ARE SHOWN BELOW THE MOUSE TO HUMAN OMICS SIGNATURES. SOME OF WHICH HAVE PREVIOUSLY BEEN NOMINATED WHICH ARE DENOTED BY THE ASTERISK AND LOOKING AT CYTOKINE AMONG OTHER READOUTS AND TESTED THESE IN MICE ALIGNED TO SUB TYPES AND SHARE THE INFORMATION OPENLY SO OUR DISCOVERY EFFORTS CAN BE EVALUATED BY THE GREATER RESEARCH COMMUNITY. AND WITH THAT, I WANT TO THANK YOU ALL FOR YOUR ATTENTION AND THE NIA FOR THEIR SUPPORT AND THE VISION FOR ENHANCING OPEN AND COLLABORATIVE RESEARCH TOWARDS PREVENTION AND TREATMENT OF AD. IT'S MADE A TREMENDOUS IMPACT ON THE CULTURE WHERE SHARING AND INCLUSION ARE EXPECTED AS THE NORM. NOW, YOU'LL HEAR FROM SEVERAL SPEAKERS THAT HAVE PIONEERED APPROACHES FOR DECONSTRUCTING COMPLEXITY TO ADVANCE PRECISION MEDICINE APPROACHES AND OUR FIRST SPEAKER IS ALLISON GOATE. GOOD MORNING EVERYONE, IÍD LIKE TO THANK THE ORGANIZERS FOR INVITING ME TO PARTICIPATE IN THE ALZHEIMERÍS DISEASE RESEARCH SUMMIT IN 2021.SO TODAY IÍM GOING TO BE TALKING ABOUT HOW GENETICS IS LEADING US TO NOVEL TARGETS. HERE WE HAVE AN EXAMPLE OF A MANHATTAN PLOT, WHICH ILLUSTRATES THE P-VALUE ON THE Y-AXIS AND POSITION WITHIN THE GENOME VARIANCE. AND THIS IS A GENOME-WIDE ASSOCIATION IN EUROPEAN POPULATIONS, WHICH HAVE IDENTIFIED MORE THAN 40 LOCI NOW THAT ARE ASSOCIATED WITH RISK FOR DISEASE.AND COMBINING THE INFORMATION FROM THE LOCATION OF THESE SNPS WITHIN THE GENOME HAS IMPLICATED THESE DIFFERENT PATHWAYS, IMMUNE RESPONSE, REGULATION OF ENDOCYTOSIS, AND CHOLESTEROL TRANSPORT IN BIOLOGICAL MECHANISMS THAT UNDERPIN AD RISK.SO, THE STUDIES THAT I SHOWED YOU THERE ARE THE ONES THAT ARE LISTED ON THE UPPER PART OF THIS SLIDE HERE. AND YOU CAN SEE THAT AS THE SAMPLE SIZE INCREASE, WE INCREASE THE NUMBER OF LOCI THAT WE IDENTIFY THAT WERE ASSOCIATED WITH DISEASE RISK. IN PRE-PRINT SERVERS NOW THERE ARE TWO ADDITIONAL MANUSCRIPTS AVAILABLE WHERE THE SIZE OF THE SAMPLES HAVE BEEN INCREASED SUBSTANTIALLY FURTHER, AND AGAIN MORE LOCI HAVE BEEN IDENTIFIED AS ASSOCIATED WITH RISK.SO WE CAN SEE THAT AS WE ADD MORE AD RISK COINCIDING IN EUROPEAN POPULATIONS, WE CAN SUBSTANTIALLY INCREASE THE NUMBER OF DISEASE LOCI IDENTIFIED.IN CONTRAST, OUR STUDIES IN NON-EUROPEAN POPULATIONS ARE MUCH SMALLER AND HAVE RESULTED IN FAR FEWER LOCI. AND YOU CAN SEE HERE ON THE TOP, A GWAS FROM KUNKLE ET AL IN 2020, WHERE THERE WERE ABOUT, JUST UNDER 3000 AFRICAN-AMERICAN CASES, AND ABOUT 5000 CONTROLS. AND THIS IDENTIFIED EIGHT NOMINALLY SIGNIFICANT LOCI THAT ARE ILLUSTRATED HERE, INCLUDING APOE.SIMILARLY IN JAPANESE POPULATION, YOU CAN SEE A STUDY PUBLISHED EARLIER THIS YEAR. ABOUT 4000 CASES, AND 4000 CONTROLS, LED TO NINE LOCI THAT WERE NOMINALLY ASSOCIATED WITH DISEASE, AND THREE WHICH REPLICATED. AND YOU CAN SEE THOSE THREE ILLUSTRATED HERE.SO, COMPARED WITH EUROPEAN POPULATIONS, THESE NON-EUROPEAN POPULATIONS HAVE MUCH SMALLER SAMPLE SIZES, AND RESULT IN IDENTIFICATION OF FAR FEWER GENES. AND NOW I WANT TO ILLUSTRATE TO YOU WHY ITÍS PARTICULARLY IMPORTANT THAT WE STUDY THESE DIVERSE POPULATIONS, BECAUSE FOR GENES THAT WE ALREADY KNOW ABOUT, WE CAN SEE THAT THE EFFECT SIZES DIFFER ACROSS POPULATIONS, AND SOMETIMES WE WILL DETECT ONE GENE IN A POPULATION, AT GENOME-WIDE SIGNIFICANCE, BUT NOT IN A DIFFERENT POPULATION.AND IF YOU LOOK AT, YOU CAN SEE HERE IN THESE THREE POPULATIONS, THESE THREE DIFFERENT GENES, THE ODDS RATIOS ASSOCIATED WITH RISK FOR APOE4 ARE DRAMATICALLY DIFFERENT ACROSS THE THREE POPULATIONS. AND THATÍS ILLUSTRATED BY GENOTYPE ON THE BOTTOM HERE, WHERE IT VARIES FROM AN ODDS RATIO FROM ABOUT TWO IN HISPANICS FOR E4 FOR GENOTYPE, TO 40 IN THE JAPANESE POPULATION, WITH AFRICAN-AMERICANS AND CAUCASIANS BEING IN-BETWEEN.WE SEE SIMILAR EFFECTS FOR ABCA7 AND SORL1. AND THIS REALLY UNDERLINES THE IMPORTANCE FOR STUDYING THE GENETICS OF DIFFERENT POPULATIONS THROUGHOUT THE WORLD, SO THAT WE HAVE A BETTER UNDERSTANDING OF THE GLOBAL GENETIC RISK FOR ALZHEIMERÍS DISEASE.SO FOR MOST OF THESE LOCI, THERE ARE NOT CODING VARIANTS IN SPECIFIC GENES THAT ARE ASSOCIATED WITH DISEASE. AND SO ONE OF THE CHALLENGES TO THE FIELD HAS BEEN TO GO FROM THESE GWAS SIGNALS TO IDENTIFYING THE SPECIFIC GENES AND VARIANTS AND HOW THEY AFFECT BIOLOGY TO IMPACT RISK. SO THIS IS A MULTI-STEP PROCESS, WHICH IS ILLUSTRATED HERE. THE FIRST THING WE NEED TO UNDERSTAND IS WHICH CELL-TYPES ARE IMPORTANT FOR THIS GENETIC RISK. AND ONCE WE UNDERSTAND WHICH CELL-TYPES, WHAT GENES WITHIN THOSE CELL-TYPES ARE AFFECTED. AND TO DO THIS WE NEED TO INTEGRATE THIS GENETIC DATA WITH INFORMATION ABOUT GENE EXPRESSION AND REGULATION, TO BE ABLE TO IDENTIFY THE SPECIFIC GENE, AND THEN WE CAN INTEGRATE THAT INFORMATION TO IDENTIFY WHICH BIOLOGICAL MECHANISMS WITHIN THE CELL ARE IMPORTANT FOR THAT RISK.SO THIS SLIDE HERE FROM NOTT ET AL IN 2019 ILLUSTRATES VERY NICELY THE IMPORTANCE OF A SPECIFIC CELL TYPE IN AD RISK. SO HERE YOU CAN SEE, THIS IS EPIGENETIC ANNOTATIONS ACROSS DIFFERENT CELL TYPES WITHIN THE BRAIN, INTEGRATED WITH GENETIC RISK FOR DIFFERENT DISEASES. AND HERE IN THESE TWO COLUMNS HERE, YOU CAN SEE TWO DIFFERENT AD GWAS STUDIES, AND SPECIFICALLY, SO THE COLOR SHOWS THE LEVEL OF ENRICHMENT, AND AD RISK VARIANCE ARE SPECIFICALLY ENRICHED ENHANCERS WITHIN MICROGLIA, AND NOT OTHER CELL TYPES.SO ONCE WE KNOW THAT, WE CAN THEN TAKE DATA, GENE EXPRESSION DATA, HISTONE ACTIVITY DATA, FROM MICROGLIA CELLS, AND ASK WHETHER THE VARIANTS THAT ARE ASSOCIATED WITH DISEASE RISK, ARE ALSO ASSOCIATED WITH HISTONE ACTIVITY, OR EXPRESSION QTLS, IN MICROGLIA. AND THAT THEN ALLOWS US TO LINK THE AD RISK VARIANT THROUGH THESE DIFFERENT STEPS, AS ILLUSTRATED ON THE RIGHT, TO DISEASE RISK.AND THATÍS EXACTLY THE KIND OF APPROACH THAT WAS TAKEN HERE BY NOVIKOVA ET AL, WHERE THEY INTEGRATED DATA NOT ACTUALLY WITH MICROGLIAL DATA, BUT WITH MYELOID CELL DATA FROM MACROPHAGES AND MONOCYTES, THAT ARE RELATED TO MICROGLIA IN THE BRAIN, AND WERE ABLE TO IDENTIFY A SERIES OF GENES WITHIN THESE AD RISK LOCI WHERE EITHER EXPRESSION WAS ASSOCIATED WITH HIGHER RISK, AND HIGHER EXPRESSION WITH HIGHER RISK, IN THE CASE OF THE RED DOTS, OR LOWER EXPRESSION ASSOCIATED WITH HIGHER RISK, IN THE CASE OF THE BLUE DOTS.AND IN THE CASE OF THE GOLD SIGNALS, THESE WERE GENES WHERE THE GENE WAS LINKED TO RISK, BUT WE WERE UNABLE TO IDENTIFY THE DIRECTION OF EFFECT. SO NOW WE HAVE 20 GENES WITHIN THESE RISK LOCI, WHERE WE BELIEVE THAT THEY ARE THE GENES RESPONSIBLE FOR ALTERING AD RISK.IF WE NOW ASK WHICH CELL TYPES, IÍM SORRY, WHICH PATHWAYS WITHIN THE CELL, MICROGLIAL CELLS, ARE THESE VARIANTS AND GENES ASSOCIATED WITH, BOTH RARE VARIANTS IDENTIFIED FROM WHOLE GENOME SEQUENCING AND WHOLE EXOME SEQUENCING, AND COMMON VARIANTS FROM THE SNP ARRAYED GWAS THAT I JUST SHOWED YOU, POINT TO EFFEROCYTOSIS, A PATHWAY INVOLVED IN CLEARANCE OF LIPID RICH DEBRIS AND DYING CELLS, AS A DISEASE RISK HUB, IN ALZHEIMERÍS DISEASE.AND YOU CAN SEE HERE THE DIFFERENT STEPS, FOUR DIFFERENT STEPS INVOLVED IN THESE EFFEROCYTOSIS PROCESS, INCLUDING RECOGNITION, ENGULFMENT, DIGESTION, AND THEN RESPONSE OF THE CELL, AND THAT THERE ARE AD GWAS GENES, AND AD VARIANT GENES ASSOCIATED WITH RARE VARIANTS, POSITIONED IN ALL OF THESE FOUR STEPS, WITHIN THE EFFEROCYTOSIS PATHWAY.WE ALSO, ON THE RIGHT, YOU CAN SEE THAT WE HAVE IDENTIFIED A NUMBER OF TARGETS THAT HAVE GONE THROUGH TO CLINICAL TRIALS, SO THEYÍRE BIOLOGICS, AND SMALL MOLECULES, TREM2, CD33, AND APOE, AND THEN THREE OTHER GENES THAT ARE NOW ALSO BEING STUDIED IN PRE-CLINICAL STUDIES, AS POTENTIAL DRUG TARGETS.DESPITE THIS SUCCESS, ITÍS ALSO IMPORTANT TO POINT OUT THAT THERE ARE SOME PRESSING NEEDS IF WEÍRE GOING TO FACILITATE THIS TARGET IDENTIFICATION AND DRUG DEVELOPMENT. AS WAS ILLUSTRATED EARLIER IN MY TALK, YOU CAN SEE THAT WE NEED MUCH LARGER SEQUENCING AND SNP ARRAY DATASETS FROM DIVERSE POPULATIONS, IF WEÍRE GOING TO UNDERSTAND THE GENETICS OF ALZHEIMERÍS DISEASE, IN POPULATIONS ACROSS THE GLOBE.SIMILARLY, WE ARE MISSING OMICS DATA FOR MYELOID AND MICROGLIAL CELLS, AND FROM SINGLE CELL DATA IN THE BRAIN, ACROSS ALL POPULATIONS. WE HAVE SOME IN EUROPEAN POPULATIONS, BUT NOT ENOUGH, AND WE CERTAINLY NEED ALL OF THIS DATA FOR NON-EUROPEAN POPULATIONS. AND THE KINDS OF DATA THAT WE NEED ARE LISTED HERE, ON THIS SLIDE. WITH THIS KIND OF INFORMATION, WE COULD REALLY SPEED UP TARGET IDENTIFICATION AND ULTIMATELY DRUG DEVELOPMENT FOR ALZHEIMERÍS DISEASE. THEN MY LAST SLIDE, IÍD JUST LIKE TO THANK THE ALZHEIMERÍS DISEASE GENETICS CONSORTIUM, THAT WAS INVOLVED IN THE GWAS STUDIES THAT I PRESENTED, THE ALZHEIMERÍS DISEASE SEQUENCING PROJECT, AND THE NEURODEGENERATION CONSORTIUM, ALL OF WHICH ARE FUNDED BY THE NATIONAL INSTITUTE ON AGING. SO, THANK YOU FOR MUCH FOR YOUR TIME. I'D LIKE TO THANK THE ORGANIZERS FOR INVITING ME TO SPEAK ON THE TOPIC OF THE DEVELOPING MULTISCALE MODELS OF ALZHEIMER'S DISEASE AND RESILIENCE. MY DISCLOSURES ARE AT THE BOTTOM RIGHT. SO, THE CHALLENGE OF THE AGING BRAIN ARE NUMEROUS; THERE ARE A PLETHORA OF DIFFERENT FACTORS THAT AFFECT THE MOLECULAR ARCHITECTURE AND FUNCTION OF THE OLDER BRAIN, FROM LIFE EXPERIENCES TO ENVIRONMENTAL EXPOSURES, PATHOLOGIES OF AGING, AND A VARIETY OF OTHER BIOLOGICAL FEATURES THAT AFFECT THE FUNCTION OF THE BRAIN. INCLUDING, VERY IMPORTANTLY BRAIN RESERVE AND RESILIENCE, WHICH ARE POSITIVE FACTORS, WHICH TEND TO HELP PRESERVE FUNCTION IN OLDER AGE. OF COURSE, THERE'S NOT A SINGLE WAY TO MEASURE ALL OF THESE DIFFERENT EFFECTS AND ALSO THE FUNCTION IN THE BRAIN. WE NEED A CONSTELLATION OF DIFFERENT TECHNIQUES TO TRY TO CAPTURE DIFFERENT LEVELS OF INFORMATION, SOME OF THEM AT THE TOP LEFT. WE CAN SEE THE MRI, WHICH IN THIS CASE, IS A FUNCTION MONITOR, CAPTURING INFORMATION ABOUT THE WAY THE BRAIN IS FUNCTIONING. THERE ARE WAYS OF CAPTURING DATA AT THE TISSUE LEVEL, AGAIN AT THE TARGET TISSUE IN ALZHEIMER'S DISEASE BRAIN, WHICH IS HERE, REPRESENTED BY THE TRANSCRIPTOME FROM THE CORTEX. IN THE BOTTOM, WE HAVE HISTOLOGIES SECTION, WITH ASTROCYTES AND MICROGLIA SURROUNDING A NERITIC AMYLOID PLAQUE. AND WE CAN SEE THAT, YOU KNOW, THESE ARE ALL PRETTY IMPORTANT DATA, INCLUDING NEW DATA, WHICH WAS SINGLE-CELL TRANSCRIPTOMIC DATA SHOWN HERE ON THE LEFT. SO, HOW DO WE BRING TOGETHER ALL THESE DIFFERENT LEVELS OF DATA? THE -- ANOTHER WAY TO LOOK AT THIS, ALSO, IS TO TRY TO SEE WHETHER WE CAN -- WHAT WE CAN UNDERSTAND IN TERMS OF THE VARIANCE IN COGNITION WITH OLDER AGE WITH WHAT'S KNOWN TODAY. IF WE LOOK AT KNOWN PATHOLOGIES, WE EXPLAIN ONLY A FRACTION OF THIS COGNITIVE AGING, AND THESE NEW MODALITIES OF DATA, INCLUDING OMIC DATA, ARE CAPTURING A LARGE PROPORTION OF VARIANCE THAT IS UNEXPLAINED TO DATE, SO THIS IS UNKNOWN BIOLOGY. THERE'S NOT, AGAIN, NOT A SINGLE MEASURE THAT CAPTURES ALL OF THE MISSING VARIANTS. WE'RE GOING TO HAVE TO HAVE DIFFERENT TYPES OF INFORMATION, WHICH CAPTURE DIFFERENT FRAGMENTS OF WHAT IS MISSING. ONE EXAMPLE I'VE SHOWN HERE, EVEN WHEN IN ONE LAYER OF INFORMATION, THE EPIGENOME. ON THE LEFT SIDE, WE HAVE A STUDY THAT LOOKED AT VERY PRECISE SINGLE NUCLEOTIDE RESOLUTION. THE DATA, WHICH FOUND CERTAIN NUCLEOTIDES WHICH WERE REPRODUCIBLY ALTERED, IN THE CONTEXT OF ALZHEIMER'S DISEASE, IN ONE REGION OF THE GENOME AND ONE SEGMENT. HOWEVER, THESE CHANGES WHICH ARE REPRODUCIBLE, ARE OCCURRING IN A WIDER CHANGE IN THE ARCHITECTURE OF THE CHROMATIN OF THE NUCLEUS, WHICH IS SHOWN ON THE RIGHT, WHICH IS USING A DIFFERENT TYPE OF PROFILING OF THE EPIGENOME, IN THIS CASE, CHROMATIN IMMUNOPRECIPITATION; WE CAN SEE THAT LARGE SEGMENTS OF CHROMATIN ARE BEING REARRANGED IN THE BRAIN IN RESPONSE TO TAU PATHOLOGY. AND SO, WE HAVE CHANGES OCCURRING AT TWO VARIED LEVELS OF FUNCTION, AND THEREFORE, WE NEED TWO DIFFERENT WAYS OF CAPTURING THIS INFORMATION, WHICH IS COMPLEMENTARY. SO, DO WE HAVE, ACTUALLY, THE DATA TODAY, TO DO A MULTISCALE MODELING? IDEALLY, WE WOULD HAVE ALL THE DATA, ALL THE LAYERS OF DATA IN A SINGLE -- EACH INDIVIDUAL, WE WOULD HAVE THIS DATA IN A LARGE NUMBER OF INDIVIDUALS, SO THAT WE COULD PROPERLY MODEL THE COMPLEX INTERCHANGE OF THE EVENTS HAPPENING IN THE COGNITIVE AGING. AND FINALLY, ALL SUBJECTS SHOULD BE RECRUITED AND CHARACTERIZED IN THE SAME SYSTEMATIC MANNER. OF COURSE, THE REALITY IS QUITE DIFFERENT. WE HAVE A COLLECTION OF HISTORICAL STUDIES THAT WERE DESIGNED FOR DIFFERENT PURPOSES; THEY'RE HETEROGENOUS IN DESIGN AND IN THE TYPE OF DATA THAT THEY COLLECT. EACH ONE OF THESE IS OF MODERATE SIZE, AND NOT SUFFICIENT TO DRIVE OUR UNDERSTANDING OF AD TODAY. AND, ALSO, THERE'S A LIMITED NUMBER OF SURE CLINICAL AND PATHOLOGICAL SCALES THAT ARE BROADLY SHARED. YEAH, SO WE ONLY HAVE A LOW-RESOLUTION ABILITY TO ALIGN THE DIFFERENT COHORTS TO ONE ANOTHER. SO, WHAT CAN WE DO WITH THE EXISTING DATA, IF ANYTHING? LUCKILY, SOME NEW METHODS, INCLUDING ARTIFICIAL INTELLIGENCE, ARE BEGINNING TO BE DEPLOYED SUCCESSFULLY IN THE EXISTING DATA. NOW, AI IS NOT A PANACEA, AND FOR MANY OF US, YOU KNOW, MANY OF ITS INTENDED USES, THE DATA WE HAVE IS NOT COMPLEX ENOUGH OR LARGE ENOUGH TO REALLY FULLY LEVERAGE THE TECHNIQUE. HOWEVER, THAT BEING SAID, THERE ARE -- THERE HAVE BEEN SUCCESSFUL DEPLOYMENTS, SUCH AS THE ONE THAT'S SHOWN HERE. WHERE WE CAN -- WE CAN USE THESE DATA, THESE APPROACHES, TO INCREASE A SAMPLE SIZE BY STITCHING TOGETHER DIFFERENT DATA SETS TO UNCOVER A HIDDEN STRUCTURE IN THE DATA THAT WE DONÍT APPRECIATE WHEN WE'RE USING OTHER METHODS, AND ALSO TO CONSIDER MULTIPLE DIFFERENT OUTCOMES SIMULTANEOUSLY. NOW, ASIDE FROM THESE METHODS, MANY DIFFERENT GROUPS OF INVESTIGATORS HAVE BEEN TRYING OTHER TYPES OF APPROACHES TO INTEGRATE DATA IN DIFFERENT WAYS. SOME OF THEM INVOLVE SIMPLE FILTERING, TRYING TO SEE HOW A RESULT, AN ASSOCIATION, PROPAGATES THROUGH DIFFERENT LAYERS OF INFORMATION, WHICH IS SHOWN AT THE TOP. WE CAN ALSO GO FROM ONE TISSUE, ONE ORGAN, THE BRAIN, TO ANOTHER ONE, LIKE THE SPINAL FLUID, IN A WAY TO TRY TO GO TOWARD TRANSLATION AND BIOMARKERS. THERE ARE ALSO INTEGRATIVE APPROACHES, WHERE WE TAKE THE DIFFERENT LAYERS OF INFORMATION OBTAINED IN A SINGLE INDIVIDUAL AND COLLAPSE ALL THIS INFORMATION INTO A SINGLE SUMMARY STATISTIC TO TRY TO BETTER -- HAVE A LIST OF BETTER-PRIORITIZED RESULTS TO GO FORWARD AND DO SOME VALIDATION. OVERALL, THE KEY HERE IS CONVERGENCE AND PROPAGATION OF FINDINGS INCREASES THE CONFIDENCE IN THE UNDERLYING OBSERVATION. ONE OF THE RESULTS OF THESE EFFORTS IS SHOWN TO THE RIGHT, WHERE WE HAVE DIFFERENT TYPES OF INFORMATION, THE GENETIC IN THE BOXES; IN THE RED CIRCLE, WE HAVE TRANSCRIPTOMIC RNA BASED DATA FROM A GROUP OF GENES THAT WORKS TOGETHER; AND THEN, IN THE BLUE BOXES, TWO DIFFERENT PATHOLOGICAL FEATURES. AND WE'VE MAPPED HOW THESE DIFFERENT MEASURES, WHICH ARE CAPTURED IN DIFFERENT WAYS, ARE INTERACTING WITH ONE ANOTHER TO ULTIMATELY CAUSE COGNITIVE DECLINE. AND THIS IS WHERE WE CAN -- WE ARE CURRENTLY BUILDING THESE MODELS TO BE LARGER AND LARGER. ANOTHER IMPORTANT QUESTION IS WHERE DO WE GO BEYOND THE BRAIN? THERE'S A LOT OF INTEREST IN CERTAIN IMMUNE CELL TYPES, AND THEIR POSSIBLE ROLE IN ALZHEIMER'S DISEASE, AND OF COURSE THEY'RE PRESENTED IN THE PERIPHERAL IMMUNE SYSTEM; ARE THEY RELEVANT? IN THIS CASE ON THE LEFT SIDE, HERE, I'VE SHOWN SOME DATA FROM RNA SEQUENCE DATA ANALYSIS FROM PERIPHERAL MONOCYTES ON THE LEFT, AND BULK RNA FROM THE BRAIN ON THE RIGHT. EACH ROW HERE SHOWS A NUMBER OF GENES ASSOCIATED WITH A PARTICULAR FEATURE, EITHER COGNITION AT THE TOP, OR PATHOLOGICAL FEATURES AT THE BOTTOM. AND WE CAN SEE THAT THE TWO TYPES OF TISSUE DO HAVE A NUMBER OF DIFFERENT ASSOCIATIONS, BUT THEY'RE DIFFERENT, THEY'RE COMPLIMENTARY. AND THIS HIGHLIGHTS HOW WE HAVE TO BEING TO BRING TOGETHER DIFFERENT TISSUES TO HAVE A MORE COMPLETE PICTURE. PART OF THIS EFFORT IS BEING UNDERTAKEN AS PART OF THE ACCELERATING MEDICINES PARTNERSHIP FOR ALZHEIMER'S DISEASE, THE AMP AD PROGRAM. SHOWN ON THE RIGHT, IS A COLLABORATION BETWEEN MULTIPLE DIFFERENT GROUPS IN AMP AD TO GENERATE DATA ON A SAME -- SAMPLES IN DIFFERENT WAYS. SO, USING MONOCYTE OR RNASEQ IN COLLABORATION WITH METABOLOMIC PROFILING, AND THEN THE METABOLOMIC PROFILING BEING CAPTURED IN CONJUNCTION WITH PROTEOMIC DATA. SO, WE AGAIN, HAVE THIS MULTIMODAL DATA CAPTURE TO BETTER UNDERSTAND TRAITS THAT ARE INVOLVED WITH COGNITIVE DECLINE IN AD.AMP AD IS ALSO SEMINAL IN BRINGING TOGETHER DIFFERENT GROUPS TO WORK TOGETHER IN MULTISCALED MODELING TO TRY TO BRING DIFFERENT EFFORTS AND DIFFERENT APPROACHES TO A SINGLE SET OF DATA. THROUGH THE AD KNOWLEDGE PORTAL, WE'VE ASSEMBLED A LARGE NUMBER OF DATA FROM THE AGING BRAIN TO FEED, YOU KNOW, THESE EFFORTS. AND ONE OF THEM IS SHOWN HERE, THAT WAS RECENTLY PUBLISHED, IN WHICH A PSEUDO TIME APPROACH WAS USED TO IDENTIFY RESILIENT INDIVIDUALS AMONGST A COLLECTION OF OLDER INDIVIDUALS, THIS SHOWS A TRAJECTORY OF AGING TOWARD DIFFERENT END POINTS. SOME PEOPLE ARE RESILIENT, BUT OTHERS END UP WITH PATHOLOGY ON THE RIGHT SIDE. AND THEN, USING THIS AS A FRAMEWORK, WE CAN NOW ADD OTHER LAYERS OF INFORMATION ON TOP TO BETTER UNDERSTAND WHAT'S GOING ON. FINALLY, MOVING UP TO SINGLE-CELL APPROACHES, ONE EXAMPLE THAT IS SHOWN HERE, WHERE WE USED THE SINGLE-CELL APPROACH TO IDENTIFY DIFFERENT SUBTYPES OF EACH CELL TYPE. SO, IN BLUE, IN THE MIDDLE OF HERE, WE HAVE SINGLE-CELL DATA FROM 24 INDIVIDUALS. THE BLUE CIRCLES ARE DIFFERENT SUBTYPES OF MICROGLIA, RED ARE ASTROCYTES, AND THE OTHER CELL TYPES ARE IN DIFFERENT COLORS. WHAT IS SHOWN HERE, ARE THE RELATIONSHIPS BETWEEN THESE DIFFERENT SUBTYPES. AND, FOR EXAMPLE, THE TOP LEFT, WE HAVE GROUP OF ASTROCYTES, ENDOTHELIAL CELLS, AND MICROGLIA, WHICH ARE ALL INVOLVED IN HOMEOSTASIS, AND THEY ARE CORRELATED TO ONE ANOTHER; THEY FORM A COMMUNITY OF CELLS IN TISSUE, AND THEY'RE INVERSELY RELATED TO ANOTHER COMMUNITY AT THE BOTTOM, ALSO COMPOSED OF OTHER TYPES OF MICROGLIA AND ASTROCYTES, WHICH ARE MORE RELATED TO ACTIVATION. AND SO, AS WE BEGIN TO IDENTIFY THIS FINE GRAIN RESOLUTION OF DIFFERENT CELLULAR COMMUNITIES OF THE MICROSCOPIC LEVEL, WE CAN PROPAGATE THIS INFORMATION INTO THE TISSUE-LEVEL DATA AS WE DID IN THIS CASE. AND USING -- TRYING TO INFER THE PROPORTION OF THESE CELL TYPES IN THE TISSUE PROFILE, WE'RE ABLE TO REPRODUCE THE CELLULAR COMMUNITIES IN THE BULK TISSUE. SO, THIS IS JUST ONE EXAMPLE OF HOW THE MULTISCALE MODELING CAN HELP TO LEVERAGE A RICH DATASET THAT IS SMALL, NOT SUFFICIENTLY POWERED FOR DISEASE ASSOCIATION, INTO A MUCH LARGER SET THAT WAS SUFFICIENT TO IDENTIFY A GROUP, A COMMUNITY OF CELLS OF THE BOTTOM IN THE RED BOX, THAT ARE INVOLVED IN ALZHEIMER'S DISEASE.SO, I'VE SHARED WITH YOU, SOME WAYS IN WHICH MULTISCALE MODEL IS BEING SUCCESSFULLY DEPLOYED BY A GROWING NUMBER OF INVESTIGATORS TO PRODUCE NEW BIOLOGICAL INSIGHTS AND AD THERAPEUTIC TARGETS. AMP AD IS DOING SOME OF THIS, BUT THERE ARE MANY OTHER INVESTIGATORS AS WELL. I'VE ALSO SHOWN HOW SOME AI METHODS ARE BEGINNING TO BE DEPLOYED SUCCESSFULLY, BUT AGAIN, IT'S NOT A PANACEA, AND WE'RE NOT QUITE THERE YET IN TERMS OF HAVING THE DATA THAT'S APPROPRIATE FOR THESE TYPES OF METHODS. SINGLE-CELL DATA OFFERS AN EXCITING NEW PERSPECTIVE, AND WE CAN PROPAGATE THE RESULTS FROM THIS HIGH-RESOLUTION INSIGHT, INTO THE EXISTING DATA WE HAVE TO DATE. HOWEVER, WE LACK THE SCALE AND COMPLEXITY OF THE DATA TO FULLY MODEL THE INDIVIDUAL'S TRAJECTORY IN AD. SO, WE NEED INVESTMENTS IN LARGER AND MORE SYSTEMATICALLY PROFILED COHORTS. WE NEED DIRECT INVESTMENT TO TRY TO BETTER UNDERSTAND THE TRAJECTORY OF AGING AND DECLINE PRIOR TO DEATH, AND ALSO COLLECT THE BRAIN OF INDIVIDUALS, BECAUSE WE HAVE YET, AT THIS POINT, TO REALLY CONNECT THE AUTOPSY MATERIAL TO THE RICH ANTEMORTEM HISTORY THAT WE COULD POTENTIALLY COLLECT ON INDIVIDUALS. FINALLY, WHILE WE DO COLLECT A LARGE NUMBER OF PATHOLOGICAL DISEASE, WE DO NOT COLLECT AS MANY INDIVIDUALS WHO HAVE AGED SUCCESSFULLY. AND SO, WITHOUT UNDERSTANDING THE VARIATION IN MOLECULAR FUNCTION AND BRAIN FUNCTION IN HEALTHY INDIVIDUALS, IT'S GOING TO BE HARD TO DISCERN WHICH PATTERNS ARE REALLY INVOLVED WITH DISEASE, AND SO OBTAINING MORE SAMPLES FROM THESE CATEGORIES OF INDUVIAL IS CRITICAL.LOOKING FORWARD, AMP AD AND OTHER PROGRAMS ARE DEVELOPING IN EXCITING NEW WAYS, BRINGING NEW LEVELS OF DATA; FOR EXAMPLE, LONGITUDINAL IMMUNOSENESCENCE PROFILES ON INDIVIDUALS WHO ARE DECLINING COGNITIVELY. AND THIS IS REALLY GOING TO BRING NEW PERSPECTIVES INTO THE WHEREWITHAL OF THE PERIPHERAL IMMUNE SYSTEM, FOR EXAMPLE IN COGNITIVE AGING. AND I WANT TO HIGHLIGHT THAT NIA HAS BEEN -- HAD A CRITICAL ROLE IN ENABLING AND ENFORCING THE RAPID SHARING OF DATA THAT HAS ENABLED A LOT OF THESE EFFORTS. BECAUSE WE ARE ASSEMBLING THE DATA IN ONE PLACE, OPTIMIZING AND REPURPOSING THE -- THERE ARE ALL KINDS OF REPURPOSING THAT CAN BE DONE BY EXTERNAL INVESTIGATORS. IN FACILITATING ACCESS TO RESULTS THROUGH THE AD KNOWLEDGE PORTAL AND THE ASSOCIATED RESOURCES, LIKE THE AD ATLAS, WHICH HAS MANY OTHER RESULTS THAT YOU CAN INVESTIGATE. WITH THIS, I'D LIKE TO THANK MY COLLEAGUES AT THE CENTER FOR TRANSLATIONAL AND COMPUTATIONAL NEUROIMMUNOLOGY, WHICH WERE INVOLVED IN THE WORK THAT I PRESENTED, SOME COLLEAGUES IN WASHINGTON STATE, AND IN JERUSALEM, AS WELL AS THE MANY COLLABORATORS IN THE AMP AD PROGRAM. THANK YOU. MY NAME IS MANOLIS KELLIS. I'M A PROFESSOR AT MIT AND AT THE BROAD INSTITUTE. AND I WOULD LIKE TO TELL YOU TODAY ABOUT OUR WORK ON DISSECTING HUMAN DISEASE CIRCUITRY IN NEURODEGENERATION AT SINGLE-CELL RESOLUTION. THE WORK IS SUPPORTED BY THE NATIONAL INSTITUTE ON AGING, AND SPECIFICALLY THE NIA PSYCH-AD PROJECT.SO, THE BASIS OF OUR WORK IS TRYING TO UNDERSTAND THE MECHANISM THROUGH WHICH GENETIC VARIANTS CONTRIBUTE IN THE CAUSAL FUNCTION TO DISEASE, IN ORDER TO UNDERSTAND THE MECHANISMS, THE TARGET GENES, THE THERAPEUTICS, AND ULTIMATELY ENABLE PRECISION AND PRECISE MEDICINE. THE CHALLENGE, HOWEVER, IS THAT THESE GENETIC VARIANTS THAT ARE ASSOCIATED WITH MOST COMPLEX DISORDERS ARE, IN FACT, BY AND LARGE MERELY EXCLUSIVELY NON-CODING. IN 93 PERCENT OF CASES, THEY DO NOT PERTURB THE PROTEINS DIRECTLY. THAT MEANS THE TARGET GENE, THE CAUSAL VARIANT, THE CELL-TYPE OF ACTION, THE RELEVANT PATHWAYS, AND THE MECHANISM THROUGH WHICH THESE VARIANTS ACT ARE SIMPLY NOT KNOWN. TO REMEDY THE SITUATION, OUR WORK -- OUR LAB COMBINES GENETIC VARIATION ACROSS COMMON AND RARE VARIANTS ASSOCIATED WITH A DIVERSITY OF PSYCHIATRIC NEURODEGENERATIVE DISORDERS AND COUPLES THESE DATA SETS WITH RNA AND EPIGENOMIC VARIATION IN BOTH HEALTHY AND DISEASE SAMPLES. WE INTEGRATE THESE DATA SETS TO PREDICT DRIVER GENES, REGIONS, AND CELL TYPES COMPUTATIONALLY, AND THEN WE EXPERIMENTALLY VALIDATE OUR PREDICTIONS IN HUMAN CELLS AND IN MOUSE MODELS, DISSEMINATE THE RESULTS, AND START THE CYCLE ALL OVER AGAIN.WE'VE APPLIED THESE TECHNIQUES TO MANY SINGLE-CELL PROFILING PROJECTS IN THE CONTEXT OF MORE THAN 1,500 BRAIN SAMPLES ACROSS 20 MILLION PLUS CELLS, ACROSS ALZHEIMER'S, FRONTOTEMPORAL DEMENTIA, LEWY BODY DEMENTIA, ALS, HUNTINGTON'S, PSYCHOSIS IN AD, SCHIZOPHRENIA, BIPOLAR, DOWN SYNDROME, AND SEVERAL OTHER DISORDERS. IN EACH OF THEM, WE PROFILE NUMEROUS INDIVIDUALS AND A TOTAL OF MORE THAN 1,500 POSTMORTEM BRAIN SAMPLES ACROSS MORE THAN A DOZEN DIFFERENT BRAIN CELL TYPES AND MULTIPLE REGIONS OF THE BRAIN AND USING BOTH RNA AND DNA ACCESSIBILITY INFORMATION.SO, THE FIRST WORK THAT WE PUBLISHED LAST YEAR SHOWED THAT SINGLE-CELL DISSECTION OF ALZHEIMER'S DISEASE CAN REVEAL GLOBAL CHANGES IN NEARLY ALL OF THE MAJOR CELL TYPES, AND SPECIFICALLY, THIS INCREASED AFFINITY OF FEMALE -- CELLS FROM FEMALE INDIVIDUALS TO BE ASSOCIATED WITH SEVERE TRANSCRIPTIONAL DYSREGULATION ASSOCIATED WITH ALZHEIMER'S DISEASE, SUGGESTING THAT THERE ARE MAJOR DIFFERENCES BETWEEN SEXES. WE ALSO FIND DRAMATIC DIFFERENCES BETWEEN EARLY VERSUS LATE CHANGES IN AD, WITH MUCH MORE CELL TYPE SPECIFIC CHANGES EARLY AND MUCH MORE GLOBAL CHANGES LATER ON, ESPECIALLY IN RESPONSE TO DNA DAMAGE. WE ALSO FOUND THAT THERE ARE THOUSANDS OF DIFFERENTIALLY EXPRESSED GENES BETWEEN MEN AND WOMEN, AND THAT NUMBER ALMOST DOUBLES IN THE CONTEXT OF AD. WE HAVE SINCE EXPANDED TO MANY ADDITIONAL BRAIN REGIONS, INCLUDING THE HIPPOCAMPUS AND THE ENTORHINAL CORTEX WHERE ALZHEIMER'S IS THOUGHT TO ORIGINATE. AND WE'VE BEEN ABLE TO DEFINE MORE THAN 30 EXCITATORY AND 23 INHIBITORY MARKERS FOR MANY ADDITIONAL SUBTYPES OF THESE NEURONS THAT ARE FOUND IN BOTH CORTICAL AND SUBCORTICAL REGIONS. WE'RE FINDING THAT BOTH EXCITATORY AND INHIBITORY NEURONS VARY GREATLY, BUT ALSO THAT GLIAL CELLS VARY DRAMATICALLY BETWEEN DIFFERENT REGIONS. WE HAVE BEEN USING THIS INFORMATION TO BUILD A TIME COURSE OF AD PROGRESSION ACROSS BRAIN REGIONS, ACROSS INDIVIDUALS, AND ACROSS INDIVIDUAL CELLS, ENABLING US TO STUDY HOW INDIVIDUAL GENES ACT EARLY, DURING, AND LATE IN THE DISEASE ONSET PROCESS. WE'VE ALSO EXPANDED INTO USING SPATIAL TRANSCRIPTOMIC DATA, SHOWING THAT, IN FACT, THE SINGLE-CELL INFORMATION CAPTURES A LOT OF SPATIAL CONTEXT FROM THE HIPPOCAMPAL FORMATION, BUT ALSO SHOWING THAT WE CAN DECONVOLVE SPATIAL TRANSCRIPTOMIC DATA INTO SINGLE-CELL RESOLUTION USING THE CONVOLUTION FRAMEWORK, ENABLING US TO NOW START IMPLEMENTING SINGLE-CELL DATA SETS WITH SPATIAL INFORMATION, BUILDING A DEEP LEARNING MODEL TO PREDICT THE SPATIAL POSITIONING OF BOTH NEURONAL AND GLIAL CELLS USING THEIR EXPRESSION PROFILES. THROUGH THE PSYCH AD PROJECT, WE'VE ALSO BEEN SPECIFICALLY LOOKING AT PSYCHOSIS IN THE CONTEXT OF AD ACROSS 231,000 CELLS IN 91 SAMPLES, INCLUDING AD WITH PSYCHOSIS, AD WITHOUT PSYCHOSIS, BOTH MALE AND FEMALE INDIVIDUALS, AND BOTH PREFRONTAL CORTEX AND HIPPOCAMPUS, AS WE SHOW HERE. AND WHAT WE'RE FINDING IS THAT THE PSYCHOSIS CHANGES ARE, IN FACT, ASSOCIATED WITH GLOBAL EXPRESSION SHIFTS IN ALL OF THE MAJOR CELL TYPES, INCLUDING EXCITATORY NEURONS FROM THE HIPPOCAMPUS AND THE PREFRONTAL CORTEX, ASTROCYTES, MICROGLIA, AND OLIGODENDROCYTES AS WELL AS OPCS.THE CHANGES ARE PREDOMINANTLY HAPPENING IN BOTH EXCITATORY NEURONS. WE BASICALLY SHOW BOTH A LOSS IN EXCITATORY NEAR PROPORTION AND ALSO A DRAMATIC DECREASE IN ACTIVITY OF EXCITATORY NEURONS BOTH IN THE PREFRONTAL CORTEX AND IN THE HIPPOCAMPUS. AND THOSE CHANGES ARE, IN FACT, ASSOCIATED WITH RIBOSOME BIOGENESIS, NEURONAL PROJECTION, AUTOPHAGY AND APOPTOSIS, SECRETION PATHWAYS, SIGNALING PATHWAYS, AND ALSO ENERGY PATHWAYS IN BOTH THE DLPFC AND THE HIPPOCAMPUS. IN THE GLIAL CELLS, WE'RE ACTUALLY FINDING CHANGE ASSOCIATED WITH CILIUM ASSEMBLY AND POSITIVE REGULATION EXPRESSION, AS WELL AS NEGATIVE REGULATION OF APOPTOTIC PROCESSES. AND SURPRISINGLY, IT SEEMS THAT THESE CHANGES ARE ASSOCIATED WITH REPRESSION RATHER THAN OVERACTIVATION, WHICH HAS BEEN THE PARADIGM THROUGH WHICH WE'RE THINKING ABOUT SCHIZOPHRENIA. THROUGH THE SAME PROGRAM, WE'VE ALSO BEEN WORKING, AS WELL AS WITH PSYCHENCODE TO UNDERSTAND THE SINGLE-CELL CHANGES THAT ARE HAPPENING IN SCHIZOPHRENIA INDIVIDUALS, AND WHAT WE HAVE FOUND IS THAT WE CAN ASSOCIATE THE VAST MAJORITY OF GENETIC RISK LOCI ASSOCIATED WITH SCHIZOPHRENIA WITH DIFFERENTIALLY EXPRESSED GENES THAT ARE EITHER POSITIVELY OR NEGATIVELY ASSOCIATED WITH SCHIZOPHRENIA, GIVING US A DIRECTION OF INTERVENTION THERAPEUTICALLY, BUT ALSO ENABLING US TO PREDICT THE CELL TYPES WHERE THESE MAXIMAL CHANGES ARE HAPPENING. AND WHAT WE'RE ALSO FINDING IS THAT FOR SUBSTANTIVE INDIVIDUALS, WE DON'T SEE THE GLOBAL GENE EXPRESSION CHANGES THAT WE SEE AS SIGNATURES OF SCHIZOPHRENIA. INSTEAD, THOSE INDIVIDUALS SHOW THIS SZTR CELL STATE, WHICH APPEARS TO BE PERHAPS ASSOCIATED WITH GLOBAL CHANGES EVEN IN ABSENCE OF TRANSCRIPTIONAL CHANGES.WE'RE ALSO ABLE TO USE THIS INFORMATION TO START PREDICTING THE UPSTREAM REGULATORS OF SCHIZOPHRENIA, AND WHAT WE'RE FINDING IS THAT IT ALLOWS US TO ACTUALLY CONNECT SYNAPTIC PROCESSES THAT ARE DYSREGULATED AND SIGNALING PROCESSES WITH NEURODEVELOPMENTAL PROCESSES WHERE THESE GLOBAL REGULATORS APPEAR TO BE ACTING BOTH EARLY IN DEVELOPMENT AND INTO AULTHOOD. WE'VE ALSO DISSECTED THE ROLE OF SYNAPTIC MICROGLIA VERSUS INFLAMMATORY MICROGLIA BY IN SILICO SORTING OF NEARLY 200,000 CELLS, AND WHAT WE'RE FINDING IS THAT THE INFLAMMATORY MICROGLIA ARE PREDOMINANTLY ENRICHED IN AD THROUGH THEIR ATAC REGIONS, OR GWAS, AND THROUGH THEIR DIFFERENTIALLY EXPRESSED GENES, OR THEIR RNA, WHILE THE SYNAPTIC MICROGLIA ARE INSTEAD ENRICHED IN SCHIZOPHRENIA GWAS VARIANTS AND SCHIZOPHRENIA DIFFERENTIALLY EXPRESSED GENES.WE'VE ALSO BEEN STUDYING THE VASCULATURE TO UNDERSTAND HOW THE BREAKDOWN OF THE BLOOD BRAIN BARRIER MIGHT ACTUALLY BE ASSOCIATED WITH DIVERSE TYPES OF NEURODEGENERATION IN BOTH ALZHEIMER'S AND IN HUNTINGTON'S DISEASE IN COLLABORATION WITH BOTH MYRIAM HEIMAN AND LI-HUEI TSAI.WE'VE BEEN LOOKING AT SINGLE-CELL ATAC DATA, BEING ABLE TO PREDICT WHAT ARE THE CELL TYPE SPECIFIC ACTIVITY OF EVERY CELL TYPE OF THESE GENE REGULATORY REGIONS AND ASSOCIATE GENE REGULATORY REGIONS WITH THEIR CANDIDATE TARGET GENES. WE'VE BEEN USING THAT TO LOOK FOR CONCOMITANT CHANGES THAT HAVE BEEN HAPPENING IN ALZHEIMER'S DISEASE BETWEEN CONTROLS AND DISEASE INDIVIDUALS, AND WHAT WE'RE SEEING IS THAT THE GENES THAT DECREASE IN EXPRESSION OR INCREASE IN EXPRESSION IN ALZHEIMER'S ARE ALSO SHOWING SIMILAR CHANGES IN DNA ACCESSIBILITY, AND WE CAN SEE THESE GLOBALLY ACROSS DOZENS OF THOSE GENES. WE'RE SEEING THAT THE GENETIC VARIANTS ASSOCIATED WITH ALZHEIMER'S DISEASE LOCALIZED VERY SPECIFICALLY IN DNA ACCESSIBILITY PEAKS FOUND IN MICROGLIA, WHEREAS THE GWAS VARIANTS ASSOCIATED WITH SCHIZOPHRENIA AND OTHER PSYCHIATRIC DISORDERS SPECIFICALLY LOCALIZED IN EXCITATORY AND INHIBITORY NEURONS, CONFIRMING OUR PREVIOUS FINDINGS. AND WE'RE ALSO ABLE TO LOOK FOR LIMITATIONS WITHIN THE RNA TRANSCRIPTS THAT WE OBTAINED FROM SMART-SEQ, FROM OLD TRANSCRIPT PROFILING, IN ORDER TO CULL LIMITATIONS AND INFER SOMATIC CHANGES THAT ARE HAPPENING IN THOSE CELLS DURING THE DEVELOPMENT OF THE BRAIN, BUT ALSO LATE IN LIFE. AND WE'RE FINDING THAT THESE CHANGES ARE ASSOCIATED WITH DIFFERENCES IN AMYLOID LEVEL AND DIFFERENCES IN COGNITION, DIFFERENCES IN SEX BETWEEN INDIVIDUALS, ENABLING US TO PINPOINT SPECIFIC PATHWAYS IN BOTH EXCITATORY NEURONS AND GLIAL CELLS THAT ARE SHOWING AN ACCUMULATION, AN INCREASED BURDEN, OF THESE SOMATIC MUTATIONS. TO TEST THESE THOUSANDS OF PREDICTIONS THAT WE'RE MAKING, WE'VE ALSO DEVELOPED HIGH THROUGHPUT WAYS OF TESTING FOR GENE REGULATORY ACTIVITY, IN THIS PARTICULAR CASE, CARRYING OUT 7 MILLION EXPERIMENTS AT A TIME USING THIS ULTRA-HIGH THROUGHPUT REPORTER ASSAYS WITH SELF-TRANSCRIBING CONSTRUCTS CAPTURED FROM THE INACCESSIBLE REGIONS. AND IT ENABLES US TO PREDICT THE NUCLEOTIDES THAT ARE DRIVING ENHANCER ACTIVITY AND LOCALIZE THEM SPECIFICALLY TO DISEASE VARIANTS. WE'VE ALSO BEEN WORKING WITH ANDREAS BENNING, LI-HUEI TSAI, AND OTHERS TO BUILD MODULAR AND PROGRAMMABLE CONSTRUCTS ENABLING US TO BOTH EDIT INDIVIDUAL SNPS, REPRESS GENES OR PROMOTERS, AS WELL AS ACTIVATE OR REPRESS ENHANCER REGIONS BY PULLING DOWN, ACTIVATING, OR REPRESSING DOMAINS WITH DCAS9. CARRYING OUT THESE CHANGES IN INDUCED PLURIPOTENT STEM CELLS DIFFERENTIATE THEM INTO THE DIFFERENT CELL TYPES, AS WELL AS CARRYING OUT IN VIVO PROFILING OF THESE CHANGES IN HIGH-THROUGHPUT REPORTER CONSTRUCTS IN THE BRAINS OF LIVING MINDS THROUGH THE CURE ALS CONSORTIUM IN COLLABORATION WITH ANDREAS. SO, THIS IS A COLLABORATION BETWEEN THE KELLIS LAB AND THE TSAI LAB, AND THERE ARE MANY, MANY FOLKS CONTRIBUTING TO BOTH THE EXPERIMENTAL WORK AND THE COMPUTATIONAL INTEGRATION. AND OUR FUNDING COMES FROM THE NIH AND THE PSYCH-AD CONSORTIUM. THANK YOU. HI, I WANT TO THANK THE ORGANIZERS FOR GIVING ME THE OPPORTUNITY TO TELL YOU A BIT ABOUT OUR WORK IN EARLY-ONSET ALZHEIMER'S DISEASE. I AM FUNDED BY THE NIH. SO, MY LAB AT UCSF IS INTERESTED IN HOW GENOMIC VARIATION CAN CONTRIBUTE TO BRAIN STRUCTURE AND FUNCTION, AND HOW THIS INTERACTS AND CAN DETERMINE BEHAVIOR AND COGNITION BOTH IN HEALTHY AGING AS WELL AS IN NEURODEGENERATIVE DISEASE. AND TODAY, I'M GOING TO FOCUS ON EARLY-ONSET ALZHEIMER'S DISEASE, OR EOAD, WHICH HAS, ADMITTEDLY, A RELATIVELY ARBITRARY FIELD ACCEPTED CUTOFF OF AN AGE OF ONSET EARLIER THAN 65 YEARS OLD. IN ADDITION TO HAVING SOME AMNESTIC FEATURES, A LOT OF EARLY-ONSET AD CASES ACTUALLY HAVE NON-AMNESTIC PRIMARY CLINICAL SYNDROMES, INCLUDING DYSEXECUTIVE FUNCTIONS, FUNCTIONAL DEFICITS, LANGUAGE PREDOMINANT VERSIONS KNOWN AS LOGOPENIC VARIANT PRIMARY PROGRESSIVE APHASIAS, AS WELL AS VISUOSPATIAL PREDOMINANT FORMS, OR POSTERIOR CORTICAL ATROPHY. IN LIGHT OF, AND NOT SURPRISING BECAUSE OF THE EARLY ONSET OF DISEASE, OFTEN THESE CASES ARE MORE CLINICALLY SEVERE OR HAVE A MUCH FASTER DISEASE TRAJECTORY AND, BECAUSE OF THE YOUNGER AGE, THE PATIENTS OFTEN SHOW UP TO AUTOPSY WITH MORE NEUROPATHOLOGICALLY PURE DISEASE OF AMYLOID BETA AND NEUROFIBRILLARY TANGLES OF TAU. AND SO, THIS CAN MAKE EARLY-ONSET AD A NICE FRAMEWORK FOR STUDYING ALZHEIMER'S DISEASE PATHOLOGY. THERE IS, HOWEVER, THIS COMMON MISCONCEPTION THAT MOST EARLY-ONSET CASES ARE FAMILIAL, WHEN IN FACT, ALMOST OVER THE 90 PERCENT OF CASES ACTUALLY DO NOT HAVE MUTATIONS IN THE MOST COMMON AUTOSOMAL DOMINANT FAMILIAL FORMS OR GENES MUTATIONS IN APP, PRESENILIN 1, PRESENILIN 2. AND, ACTUALLY, ABOUT HALF OF EOAD CASES DO NOT EVEN HARBOR THE POTENT RISK FACTOR, APOE E4.SO, IN LIGHT OF ALL OF THESE THINGS, MISDIAGNOSIS IS OFTEN VERY COMMON, AND SO ONE OF OUR INTERESTS IS REALLY TRYING TO ENHANCE DIAGNOSTIC STRATEGIES. AND SO, HERE I'M SHOWING YOU PET IMAGING DATA OF AMYLOID AND TAU, AMYLOID ON TOP, TAU ON BOTTOM. THIS IS WORK DONE BY ONE OF MY COLLEAGUES, RENAUD LA JOIE AT UCSF. AND WE SEE THAT, WHILE ALL CASES -- SO WE'RE SEEING IN OUR COLUMNS, IN OUR AMNESTIC-PREDOMINATE EARLY ONSET ADS, OUR POSTERIOR CORTICAL ATROPHY OR VISUOSPATIAL PREDOMINATE, AND THE LOGOPENIC VARIANT OR LANGUAGE PREDOMINATE. AND WE SEE THAT, ACTUALLY, THE AMYLOID PATTERNS ACROSS ALL OF THESE DIAGNOSES ARE RELATIVELY SIMILAR. HOWEVER, THE TAU PATHOLOGICAL DIFFERENCES ARE QUITE DISTINCT, AND WE SEE THE MOST TAU DEPOSITION IN RED IN THE REGIONS OF THE BRAIN THAT CORRELATE WITH THE MOST PREDOMINATE CLINICAL CHANGES IN THESE PATIENTS. AND SO, IT DOES SUGGEST THAT THERE IS SOME HETEROGENEITY UNDERLYING EACH OF THESE DIFFERENT FORMS OF EARLY-ONSET ALZHEIMER'S DISEASE. AND SO, IN LIGHT OF THE FACT THAT THESE ARE OFTEN DIFFICULT TO DIAGNOSE IN RARE CONDITIONS, WE WERE REALLY INTERESTED IN TRYING TO ADDRESS THE QUESTION OF HOW WE COULD IMPROVE DIAGNOSIS TO ENHANCE PATIENT CARE. AND IN LIGHT OF THIS OBSERVED CLINICAL HETEROGENEITY, WE HOPE TO LEARN MORE ABOUT UNDERLYING MOLECULAR DYSREGULATION ASSOCIATED WITH EACH OF THESE SUBTYPES, AND THEN APPLY THIS KNOWLEDGE TO DEVELOP NEW DIAGNOSTIC TOOLS TO ENHANCE CLINICAL CARE. I'M GOING TO GIVE YOU JUST TWO EXAMPLES OF STRATEGIES THAT WE ARE USING IN OUR CURRENT STUDIES. THE FIRST IS A TOOL THAT IS BASICALLY TAKEN FROM THE BEST EXAMPLE OF PRECISION MEDICINE THAT WE HAVE RIGHT NOW IN MEDICINE, THE CANCER FIELD. THE TECHNIQUE IS CALLED RADIO GENOMICS, AND IT INTEGRATES ANALYSIS OF RADIOLOGIC DATA OR IMAGING DATA, ALONG WITH GENETIC DATA, OFTEN GENE TRANSCRIPTION OR GENE EXPRESSION DATA. AND SO, HERE IN PANEL A, WE SEE AN EXAMPLE FROM A CANCER PAPER, WHERE WE HAVE MULTIPLE IMAGES OR CT IMAGES OF A CANCER LESION IN A PATIENT. WE CAN DO SPECIFIC FEATURE IDENTIFICATION OF THE DIFFERENT ASPECTS OF THOSE LESIONS, AND THEN CREATE A MATRIX, BASICALLY, DELINEATING EACH OF THOSE DIFFERENT FEATURES THAT WE SEE IN THE IMAGING FOR EACH OF THE PATIENTS IN THE STUDY. SIMILARLY, IN PANEL B, WE CAN TAKE GENE DATA, OR GENE EXPRESSION DATA, FROM RNA SAMPLES FROM EACH OF THE LESIONS, TO DO NEXT GENERATION SEQUENCING, AND THEN CREATE COMPILATIONS OR SUMMARIES OF THE GENE EXPRESSION PATTERNS ACROSS MANY DIFFERENT MODULES OF GENES, AND LOOK AT THOSE FOR EACH PATIENT. AND THEN, WE BASICALLY CORRELATE THOSE TWO MATRICES TO EACH OTHER TO TRY TO DIFFERENTIATE OR CLASSIFY THE PATIENTS BASED ON THE FEATURES THAT ARE MOST SIMILAR BETWEEN GROUPS AND DIFFERENT ACROSS BIGGER GROUPS. AND SO, HERE IS AN EXAMPLE WHERE WE CAN REALLY LEVERAGE THE STRUCTURAL OR NEURODEGENERATIVE PATTERNS THAT ARE DISTINCT ACROSS EACH OF OUR EO SUBTYPES, AND USE THAT INFORMATION TO CREATE A SIMILAR IMAGING MATRIX. WE CAN, THEN, COMPARE IT AND CORRELATE IT TO GENE EXPRESSION PATTERNS THAT WE'RE LOOKING AT IN THE CONTEXT OF PERIPHERAL BLOOD MONONUCLEAR CELLS, OR PBMCS, FROM THE BLOOD. AND IN THIS CASE, WE'RE USING A SINGLE CELL RNA SEQUENCING TECHNIQUE TO GET GENE EXPRESSION ACROSS DIFFERENT FORMS OF EOAD. SO, TYPICALLY, WE THINK OF, IN A SIMPLISTIC MODEL, THAT ONE GIVEN GENE IS CORRELATED WITH A SINGLE EFFECT, TRAIT, OR DISEASE. IN A POLYGENIC FRAMEWORK, WE SEE MULTIPLE GENES CORRELATED TO ONE EFFECT, DISEASE, OR TRAIT. IN PLEIOTROPY, WE HAVE A SINGLE GENE CONTRIBUTING TO MULTIPLE DIFFERENT EFFECTS, TRAITS, OR DISEASES. AND THEN WE HAVE, WHAT I LIKE TO CALL REAL LIFE, WHERE WE HAVE MULTIPLE GENES AND LOTS OF PLEIOTROPY LEVELING, YOU KNOW, ALL INTERPLAYING. AND SO, THIS IS WHERE WE SPEND MOST OF OUR TIME IN NEURODEGENERATIVE DISEASE STUDIES, AND WE CAN ACTUALLY LEVERAGE THIS PLEIOTROPIC ENRICHMENT TO IDENTIFY NEW GENES ASSOCIATED WITH EARLY-ONSET AD. AND THIS BASICALLY MEANS THAT, YOU KNOW, WE CAN LOOK AT GENES THAT ARE ASSOCIATED WITH ONE TRAIT THAT WE THINK IS RELATED TO EOAD, AND THOSE WILL ACTUALLY INCREASE THE STATISTICAL SIGNIFICANCE OR ASSOCIATION WITH EARLY-ONSET AD. AND SO, WE SEE THAT WHEN WE HAVE A GENOME-WIDE ASSOCIATION STUDY OF EARLY-ONSET AD -- THIS IS A SMALLER STUDY OF ABOUT SEVERAL HUNDRED INDIVIDUALS -- WE CAN COMPARE THAT GWAS' RESULTS WITH MANY OTHER -- WE HAVE 64 DIFFERENT TRAITS AND DISEASES GENOME-WIDE ASSOCIATION STUDY RESULTS, AND WE SEE, ACTUALLY, THAT EARLY-ONSET AD SHOWS RELATIVELY LITTLE OVERLAP WITH LATE-ONSET AD GENETIC RISK. HOWEVER, IT SHOWS A LOT OF OVERLAP, OR GENETIC ENRICHMENT, WITH GWAS OF LIPID, METABOLIC, AND IMMUNE RELATED TRAITS, AND, INTERESTINGLY, ANOTHER EARLY ONSET DEMENTIA, FRONTOTEMPORAL DEMENTIA. AND SO, WE CAN SEE HERE, THIS VENN DIAGRAM, SIMPLISTICALLY SHOWING THAT, WHILE WE PICK UP A LOT OF RISK-VARIANTS FOR LATE-ONSET AD, ONLY SEVEN OVERLAP WITH EOAD, AND THOSE ARE ACTUALLY MOSTLY IN THE APOE AND TOMM40 LOCUS. AND SO, WE HAVE ALREADY BEEN ABLE TO BEGIN TO LEVERAGE THIS 800-FOLD ENRICHMENT OF EARLY-ONSET AD AND FTD IN EFFORTS TOWARDS GENE DISCOVERY. AND WE DID THIS RECENTLY WITH COLLEAGUES AT THE HUDSON ALPHA BIOTECHNOLOGY INSTITUTE TO IDENTIFY RARE VARIANTS IN THE GENE TET2, ENRICHED FOR RISK IN MULTIPLE NEURODEGENERATIVE DISEASES. SO, OVERALL, THESE RARE VARIANTS CONFERRED ABOUT THREEFOLD INCREASE IN RISK, AND THAT WE SAW THIS IN AD AND FTD, AS WELL AS A SUGGESTIVE SIGNAL IN ALS, SO IT DOES SUGGEST THAT THERE IS SOME SHARED GENETIC OVERLAP ACROSS THESE DISEASES. BUT I THINK IT IS IMPORTANT TO NOTE THAT IN ORDER TO USE ANY OF THIS GENETIC INFORMATION TO MAKE PERSONALIZED PREDICTIONS OF DISEASE RISK, WE WILL NEED REPRESENTATION FROM ALL STUDIES FROM ALL POPULATIONS. AND SO, I REALLY URGE EVERYONE TO THINK ABOUT HOW THEY MAY BE ABLE TO ENRICH THEIR OWN GENETIC STUDIES FOR DIVERSE POPULATIONS. THANK YOU. WITH AGE, THE BRAIN BECOMES SUSCEPTIBLE TO COGNITIVE DYSFUNCTION, NEURODEGENERATION, AND IN FACT, AGE IS THE KEY RISK FACTOR FOR DEGENERATIVE DISEASES SUCH AS ALZHEIMER'S. THIS HAS PROMPTED MANY IN THE FIELD TO CONSIDER THE POSSIBILITY TO SLOW DOWN OR EVEN REVERSE AGING IN WHAT IS OFTEN TERMED AS REJUVENATION. SO, WHILE THIS IS NOT YET FEASIBLE IN HUMANS AND SOUNDS MAYBE A BIT TOO GOOD TO BE TRUE, THERE IS GROWING EVIDENCE THAT REJUVENATION MAY WORK IN MICE AND WE'VE DOCUMENTED BENEFITS EVEN ON THE BRAIN. THIS INCLUDES METABOLIC INTERVENTION, SUCH AS CALORIC RESTRICTION, EXERCISE, OR THE USE OF SMALL MOLECULES, THE REMOVAL OF SENESCENT CELLS, TRANSIENT EPIGENETIC PROGRAMMING, OR THE ADMINISTRATION OF YOUNG BLOOD OR FAT THAT'S FROM YOUNG BLOOD. SO, WHAT WILL BE NECESSARY TO TRANSLATE THIS TO HUMANS? WHAT WE BELIEVE IS THAT WE NEED TO GAIN A MOLECULAR UNDERSTANDING OF AGING TRAJECTORIES. AND WHAT I MEAN BY THAT IS THAT WE NEED TO UNDERSTAND HOW THE ORGANISM AGES, NOT JUST AS A WHOLE, BUT HOW EACH INDIVIDUAL CELL TYPE AGES, HOW TISSUES AGE, AND ALSO WE MAY BE ABLE TO HARNESS FLUIDS, AS WE WILL SEE IN A MINUTE, TO STUDY THE AGING PROCESS. AND THIS CAN BE DONE BY EXPLORING CHANGES AT THE EPIGENOME, PROTEOME, TRANSCRIPTOME, LIPIDOME, OR METABOLOME LEVELS. AND SO, ONE EXAMPLE WOULD BE TO STUDY HOW THE COMPOSITION OF THE BLOOD CHANGES WITH AGE. AND HERE, WE HAD THE OPPORTUNITY TO COLLABORATE WITH THE INTERVAL COHORT WITH NIR BARZILAI AND HIS LONGENITY COHORT TO COLLECT BLOOD SAMPLES FROM OVER 4,000 HEALTHY PEOPLE AGED 20 TO 100. AND WE MEASURED CLOSE TO 3,000 PROTEINS WITH SOMALOGIC PLATFORM. AND THIS IS BASICALLY SHOWING YOU THE SUMMARY OF THIS WHOLE EXPERIMENT, WHERE IN BLUE YOU SEE LOW LEVELS OF A PROTEIN, CHANGES TO THE YELLOW WOULD BE HIGH LEVELS. AND WHAT YOU SEE IMMEDIATELY IS THAT AGE IS NOT LINEAR. THERE'S DRAMATIC CHANGES HAPPENING WITH AGE. WE CAN ALSO ASK AT EACH AGE, WHAT ARE THE PROTEINS THAT CHANGE FROM YOUNGER PEOPLE TO OLDER PEOPLE AND HOW MANY PROTEINS CHANGE AT A GIVEN AGE. AND IF WE SUM THESE UP, YOU GET SOMETHING LIKE A MOUNTAIN RANGE HERE WE CALL "WAVES OF AGING." SO HERE, FOR EXAMPLE, WE HAVE SEVERAL HUNDRED PROTEINS THAT ARE SIGNIFICANTLY DIFFERENT BETWEEN PEOPLE YOUNGER THAN 35 COMPARED TO PEOPLE OLDER THAN 35. THERE'S ANOTHER WAVE AT AROUND 65 YEARS OF AGE, AND THEN THE MOST PROMINENT ONE AT AGE 80. AGAIN, BRINGING HOME THIS KEY MESSAGE THAT AGE IS NOT LINEAR, IT'S ASYNCHRONOUS. INTERESTINGLY, VERY SIMILAR RESULTS WERE OBTAINED WITH A COMPLETELY DIFFERENT METHOD BY LOOKING AT EPIGENETIC CHANGES JUST IN BLOOD CELLS, SO NOT AT THE WHOLE SORT OF ORGANISM LEVEL THAT THE PLASMA CAN DO. AND THIS STUDY, AGAIN, CAME TO THE CONCLUSION THAT THERE ARE BREAK POINTS, HOW THEY CALLED THEM, BOTH IN FEMALES AND MALES THAT OCCUR AROUND 40 YEARS OF AGE AND AROUND 60 TO 70 YEARS OF AGE. THERE'S THREE DIFFERENT COLORED LINES HERE ARE THE GROUPS OF CHANGE THAT CHANGE SORT OF IN SYNCHRONY. BUT AGAIN, YOU SEE THESE WAVES OF AGING APPARENTLY. WE DON'T KNOW YET WHAT THEY MEAN, BUT IT'S DEFINITELY SOMETHING WE WANT TO EXPLORE. WE CAN ALSO STUDY TRANSCRIPTIONAL CHANGES WITH AGE. AND HERE WE HAD THE OPPORTUNITY TO COLLABORATE WITH STEVE QUAKE AT THE CHAN ZUCKERBERG INITIATIVE TO LOOK AT TRANSCRIPTIONAL CHANGES BOTH AT THE BULK LEVEL, BUT ALSO THE SINGLE-CELL LEVEL IN 20 DIFFERENT TISSUES FROM THE MOUSE AS IT AGES. AND THAT HAS LED TO A SERIES OF PUBLICATIONS THAT ALLOW YOU TO LOOK AT EVERY CELL TYPE, WHERE THE GENE -- WHERE A GIVEN GENE IS EXPRESSED, AND HOW THEY CHANGE WITH AGE. AND JUST A FEW TAKE HOME MESSAGES FROM THIS STUDY. AN EXAMPLE -- PROMINENT EXAMPLE IS GONADAL ADIPOSE TISSUE THAT SORT OF ILLUSTRATES THE CHANGES THAT WE SEE WITH AGING. HERE, THIS IS AT THE BULK MRNA LEVEL WHERE YOU SEE, AGAIN, NONLINEAR CHANGES OCCURRING WITH AGE. GONADAL ADIPOSE TISSUE ACTUALLY SHOWING SOME OF THE EARLIEST CHANGES IN ADULTHOOD. AND THEN, YOU CAN LOOK AT THAT AT AN INDIVIDUAL TISSUE LEVEL - BOTH GENES THAT GO DOWN OR GENES THAT GO UP, AND YOU SEE THAT NOT EVERY TISSUE SHOWS THE SAME CHANGES, AND YOU SEE SORT OF THESE PROGRESSIVE CHANGES AS THE ANIMALS GET OLDER. AND THAT REALLY LED TO THE REALIZATION WHICH WAS ACTUALLY PUT FORTH MORE THAN 20 YEARS AGO BY MONICA DRISCOLL THAT TISSUES DO NOT AGE IN SYNCHRONY IN AN ORGANISM. WE DON'T KNOW EXACTLY WHY THEY DON'T DO THAT. THIS MAY BE IN PART DUE TO STOCHASTIC BUT ALSO GENETIC AND ENVIRONMENTAL EFFECTS. BUT YOU CAN SEE THAT SOME TISSUE -- SO THE MOST DRAMATIC CHANGE IS EARLY DURING THE REPRODUCTIVE PHASE STILL. THEN, FAT TISSUE, AS I MENTIONED EARLIER, SORT OF THE FIRST TISSUE THAT STARTS TO CLEARLY CHANGE FROM A HOMEOSTATIC GENE EXPRESSION TO THESE AGE RELATED CHANGES. AND THEN OTHER TISSUES CHANGE MUCH LATER IN GENE EXPRESSION. WE CAN ALSO LOOK AT THAT OTHER CELL TYPE LEVEL. AND SO, THIS, WHAT WE CALL A PICASSO CLOCK, SHOWS ALL THESE DIFFERENT CELL TYPES IN THE DIFFERENT ORGAN TISSUES. AND SO HERE, EACH SIZE OF DOT REFLECTS THE NUMBER OF GENES THAT CHANGE IN THIS GIVEN CELL TYPE. FOR EXAMPLE, HERE, THE FIBROBLAST IN THE TRACHEA - HOW MANY GENES CHANGE WITH AGE IN THIS CELL TYPE? AND THEN THE LINES CONNECT THE CELLS THAT SHOW SIMILAR CHANGES IN THE TOP GENE. SO, YOU COULD SAY THESE CELLS SHOW SIMILAR AGING TRAJECTORIES. AND THESE ARE TWO INTERESTING OBSERVATIONS. HIGHLIGHTED HERE AND THESE ARE TWO INTERESTING OBSERVATIONS. HIGHLIGHTED HERE IN YELLOW FIRST, FOR SORT OF CELL TYPE SPECIFIC CHANGES. SO, THESE CELLS, NO MATTER IN WHICH TISSUE, THE STROMA CELLS FOR EXAMPLE, THEY SHOW SIMILAR CHANGES WITH AGE. LIKEWISE, ENDOTHELIAL CELLS IN DIFFERENT TISSUES INCLUDING BRAIN, DIAPHRAGM, FAT TISSUES, AND SO FORTH, THEY SHOW SIMILAR CHANGES WITH AGE. BUT THEN WHAT YOU ALSO NOTE IS THAT THERE ARE TISSUES THAT SEEM TO SHOW CHANGES IN DIFFERENT CELL TYPES THAT ARE SYNCHRONIZED. AND EXAMPLES HERE WOULD BE THE SKIN, WHERE DIFFERENT CELL TYPES SUCH AS KERATIN CELLS, EPIDERMAL CELLS, BASAL CELLS, SEEM TO SHOW SIMILAR TOP GENES THAT CHANGE WITH AGE. LIKEWISE, IN THE PANCREAS. THE GAPS THAT WE NEED TO STILL ADDRESS ARE THAT CELLULAR AND BRAIN REGIONS SPECIFIC MOLECULAR TRAJECTORIES OF HUMAN OR MOUSE BRAIN AGING NEED TO BE ESTABLISHED AND NEED TO BE MEASURED. WE WANT TO KNOW - WHAT ARE THE MOLECULAR SIMILARITIES BETWEEN NORMAL BRAIN AGING AND ALZHEIMER'S DISEASE PATHOGENESIS? HOW DOES THE BRAIN AGE RELATE TO AGING OF THE ORGANISM AS A WHOLE? AND COULD THE BIOLOGICAL AGE OF A BRAIN PREDICT MAYBE THE DEVELOPMENT OF NEURODEGENERATION? THANK YOU VERY MUCH. FIRST I WOULD LIKE TO THANK THE NATIONAL TINS INSTITUTE OF AGING AND FOOR THE OPPORTUNITY TO PRESENT THE TALE OF TWO SYSTEMS AND THE LESSONS LEARNED FROM MID LIFE AGING THAT HAVE IMPLICATIONS FOR ALZHEIMER'S PREVENTION AND TREATMENT. THROUGHOUT MY TALK, I WILL BE PRESENTING KEY CONCEPTS THAT HAVE EMERGED FROM OUR PROGRAMS OF RESEARCH. THE FIRST OF THOSE IS THAT THERE ARE THREE AGING PROGRAMS DURING MID LIFE. EARLY CHRONOLOGICAL AND ENDOCRINEOLOGICAL. THAT STARVATION RESPONSE ACTIVATES MULTIPLE ADAPTIVE RESPONSES. THAT IS KICK STARTED BY A DECLINE IN GLUCOSE METABOLISM FOLLOWED BY A DECLINEAMINO ACID METABOLISM. FOLLOWED BY A RISE IN FATTY ACID BETA OXIDATION AND KETONE BODY METABOLISM. THIS WAS DERIVED FROM OUR DISCOVERING SCIENCE AND TRANSLATED TO HUMAN SCIENCE, THE WORK BEING DONE BY DR. MUSCONI IN OUR PROGRAM PROJECT. WHAT SHE HAS FOUND FOLLOWING OUR SAME ENDOCRINELOGICAL, IN THE TEMPORAL CORTEX, PREFRONTAL CORTEX. INVESTIGATING THE DECLINE IN PHOSPHORYLATION UTILIZING, WHAT WE FIND IS ALZHEIMER'S RELATIVE TO NORMAL AGING SHE A DECLINE IN NUCLEAR TRANSCRIPTOME. COMPENSATORY RISE IN THE TRANSCRIPTOME DOWN REGULATION REQUIRED FOR OXIDATIVE PHOSPHORYLATION PROTEIN. FURTHER, THERE'S AN UNCOUPLING BETWEEN THE MITOCHONDRIAL COMPONENT. WE THEN ASK THE QUESTION, WHAT IS THE SOURCE OF THESE KETONE BODIES AND WHY IS BETA OXIDATION. OUR DISCOVERY RESEARCH HAS DETAILED THIS ENTIRE PROCESS IN WHICH THE DECLINE IN GLUCOSE METABOLISM ACTIVATES A COMPENSATORY RISE IN BETA OXIDATION AND KETOGENESIS FROM LIPIDS. SO LIPIDS ARE ACTUALLY CONTRIBUTED FROM METABOLISM OF THE WHITE MATTER. AND THAT WHITE MATTER IS CONVERTED INTO FATTY ACID AND ULTIMATELY KETONE BODIES TO GENERATE ACETYLCHOLINE. PART OF THAT METABOLISM IS THE GENERATION OF MYELIN DEBRIS, MICRO GLIA AND THEN PRESENTED AS AN ANTIGEN ON THE SURFACE OF MICRO GLIA THAT THEN ACTIVATES INFILTRATION OF T-CELL LIMB PO SITES FROM THE PERIPHERY AND ACTIVATION OF AN AUTOIMMUNE RESPONSE. TO MYELIN DEBRIS. AGAIN, THIS IS SUPPORTED IN THE HUMAN ANALYSES, BRAIN IMAGING DECREASE THE EFFIGY PET IN THE FEMALE BRAIN, DECLINE IN WHITE MATTER VOLUME AND RISE IN BETA AMYLOID DEPOSITION. AND HERE YOU SEE THE PROGRESSIVE DEGENERATION OF WHITE MATTER FROM COMPACT TO DISINTEGRATED TO A LOSS OF MYELIN. WE THEN WENT ONTO ASK WHETHER THERE CLEARLY, THIS IS INDICATING AN INTERACTION BETWEEN THE METABOLIC SYSTEM AND THE IMMUNE SYSTEM AND WHAT WE FIND IS THAT EARLY IN CHRONOLOGICAL AGING THERE'S A RISE IN THE INNATE IMMUNE SYSTEM FOLLOWED BY A RISE IN THE ADAPTIVE IMMUNE SYSTEM THAT IS SUSTAINED IN LATE CHRONOLOGICAL AGING AND CONTINUES. THE QUESTION IS WHAT IS THE PURPOSE AND FOR THAT, THESE TWO SYSTEMS ESSENTIALLY HAVE ONE PURPOSE AND THAT IS TO FEED A STARVING BRAIN. WHEN WE LOOK AT THE METABOLIC REPROGRAMMING, AGAIN WHAT WE FIND IS THE METABOLIC AND IMMUNE SYSTEMS ARE INDEED PARTNERS IN THIS METABOLIC REPROGRAMMING THAT INVOLVES BOTH THE ASTRO SITES AND MICRO GLIA AND T-LYMPHOCYTES IN SPOONS. GOING FORWARD, WHAT WE ASKED IS THERE A SEX DIFFERENCE. AND AGAIN THIS RECA -- RECAPITULATES OUR FINDING IN THE MID LIFE FEMALE BRAIN, DECLINE IN WHITE MATTER VOLUME AND BETA AMYLOID DEPOSITION. AND THAT IS MANIFESTED IN THE PERIPHERAL ME TAB LOEM HERE IN INDIVIDUALS WOMEN WITH ALZHEIMER'S SHOWING AN ELEVATED -- PROFILE VERSUS THE MALE PROFILE WHICH IS CHARACTERIZED BY BRANCHED AMINO ACIDS AND A MEANS WHICH COULD BE CONVERTED TO GLUCOSE TO FEED A STARVING BRAIN. WE ASK WHETHER THERE'S AN IMPACT OF APOE GENOTYPE. WE FIND INDEED THAT THE APOE FOR MALE BRAIN HAS HIGHER LEVEL OF GLUCOSE METABOLISM RELATIVE TO THE FEMALE. THAT IS TRUE IN THE MALE, LONGITUDINAL ANALYSIS SHEEN HERE ACROSS THREE YEARS THAT THE FEMALE HAS A LOWER -- GENE EXPRESSION, ARISE IN THE IMMUNE RESPONSE, ARISE IN INDICATORS OF DEVELOPMENTIVE AUTOIMMUNITY AND RISE IN THE INFILTRATION OF T-LYMPHOCYTES IN THE BRAIN FROM THE PERIPHERY ALL OCCURRING DURING MID LIFE. WE THEN HAVE ASKED HOW DOES THIS IMPACT OUR UNDERSTANDING FOR THERAPEUTIC INTERVENTIONS? AND WHAT WE FIND IS THAT LIPID LOWERING AGENT STATINS HAVE A SIGNIFICANT -- CAN SIGNIFICANTLY REDUCE THE RISK OF DEVELOPING ALZHEIMER'S AND DEMENTIA AS WELL AS M.S., PARKINSON'S AND A.L.S. TO A LESSER EXTENT, INTERVENTIONS FOR TYPE II DIABETES, GLUCOSE REGULATING THERAPIES ALSO CAN REDUCE THE RISK OF ALZHEIMER'S DISEASE IN LATER LIFE. AS WELL AS ANTI-INFLAMMATORIES INDICATING EARLIER STUDIES, HORMONE, ESTROGEN-BASED STUDIES, AS ESTROGEN REGULATES GLUCOSE METABOLISMS AND SUPPRESSES IMMUNE RESPONSES. THE QUESTION THEN BECOMES HOW WELL DO THESE RISK FACTOR TREATMENTS IN MID LIFE TRANSLATE TO TREATMENT AND THERE HAS BEEN A MIXED RESPONSE. WHAT I WILL SAY IS THAT, WE DID CONDUCT AN ANALYSIS WITH DR. GAIFMAN WHO DID A RESPONDER ANALYSIS ACROSS MULTIPLE FAILED CLINICAL TRIALS AND FOUND THAT IN THE STATIN TRIAL THERE WERE INDEED RESPONDERS AND THEY WERE THEREFORE CARRIERS. ESSENTIALLY, PREVENTION CAN UTILIZING THERAPIES THAT REDUCE THE RISK OF DEVELOPING ALZHEIMER'S DISEASE AND TARGETING RISK FACTORS FOR ALZHEIMER'S DISEASE ARE BENEFICIAL IN MID LIFE AND HAVE MIXED RESULTS AT BEST LATER IN LIFE IN PERSONS WITH ALZHEIMER'S. WE THEN ASKED THE QUESTION OF HOW WE CAN DEVELOP PRECISION MEDICINE FOR ALZHEIMER'S DISEASE. AND CLEARLY, WE ARE GOING TO HAVE TO FOCUS ON THE STAGE OF THE DISEASE, WHETHER THIS IS A PREVENTION OR DELAY OR TREATMENT INTERVENTION BASED ON THE IMMUNE AND METABOLIC PROFILES. THE SEX OF THE INDIVIDUAL CHROMOSOMAL AND APOE GENOTYPE. AND CLINICAL PROFILE NEEDS TO BE CONSIDERED IF THIS PERFECT IS HYPER TENSIVE OR TYPE II DIABETIC OR TRAUMATIC BRAIN INJURY. TAKING TOGETHER THESE FACTORS THAT ARE TRACKABLE HAS THE POTENTIAL TO SIGNIFICANTLY ADVANCE PRECISION MEDICINE FOR ALZHEIMER'S DISEASE. IN CONCLUSION, OUR WORK HAS SHOWN THAT MID LIFE AGING TRANSITIONS CAN BE A TIPPING POINT FOR DEVELOPING LATE ON SET ALZHEIMER'S DISEASE. THAT THE BRAIN CAN UNDERGO A STARVATION EPISODE IN MID LIFE AND THAT TO ACTIVATE THE COMPENSATORY AUXILIARY FUEL SYSTEMS TO SUSTAIN BRAIN FUNCTION AND THAT THEY CAN UTILIZE THE LIPID RESERVOIR OF WHITE MATTER, BOTH METABOLIC AND IMMUNE SYSTEM APPEAR TO FUNCTION WITH ONE PURPOSE THAT, IS TO FEED A STARVING BRAIN. AND TOGETHER, THESE TWO SYSTEMS REGULATE METABOLIC REPROGRAMMING. CHROMOSOMAL SEX MATTERS, APOE GENOTYPE MATTERS. THERE'S A CLEAR PATH FOR ADVANCING PRECISION PREVENTION AS WELL AS TREATMENT FOR ALZHEIMER'S DISEASE. I WANT TO ESPECIALLY RECOGNIZE AND APPRECIATE THE PROGRAM ANNOUNCEMENTS AND NOTICES THAT HAVE BEEN DEVELOPED FROM PREVIOUS ALZHEIMER'S SUMMIT MEETINGS AND THAT HAS SUPPORTED THE RESEARCH THAT I HAVE JUST PRESENTED. LASTLY, I WANT TO ACKNOWLEDGE MY TEAM WHO ARE EXCEPTIONAL. OUR COLLABORATORS, OUR WONDERFUL COLLABORATORS AND ESPECIALLY OUR SPONSORS AND ESPECIALLY THE NATIONAL INSTITUTE ON AGING. THANK YOU. >> HELLO, AGAIN. WOW, I HOPE YOU ALL ENJOYED THESE VERY COMPREHENSIVE AND STIMULATING TALKS. SO TERRIFIC TO SEE THE PROGRESS TOWARDS UNDERSTANDING COMPLEXITY JUST IN THE LAST THREE YEARS. I WANTED TO SAY BEFORE WE GO ON BREAK, I JUST WANT TO REMIND EVERYONE AND ENCOURAGE YOU, THAT THE AUDIENCE SUBMIT QUESTIONS OR COMMENTS TO THE FEEDBACK BUTTON ON THE N.I.H. VIDEOCAST SCREEN WHEN YOU ARE WATCHING AND WHEN SUBMITTING YOUR QUESTION PLEASE INDICATE WHICH SPEAKERS YOU WANT TO DIRECT THEM TO. AND COME BACK AND JOIN US FOR THE LIGHTNING ROUND AFTER THIS BREAK. THAT WILL BE FOLLOWED BY THE PANEL Q&A SESSION. SO THANK YOU FOR YOUR ATTENDANCE AND WE WILL SEE YOU SOON. SEX-SPECIFIC DIFFERENCES IN ALZHEIMER'S DISEASE, THE X CHROMOSOME MATTERS. SEX DIFFERENCES EXIST IN ALZHEIMER'S DISEASE, AND THERE ARE DIFFERING VULNERABILITIES IN MEN AND IN WOMEN. MORE WOMEN LIVE WITH ALZHEIMER'S DISEASE, IN PART DUE TO THEIR LONGEVITY WITH THE DISEASE. WOMEN LIVE TO ADVANCED AGES WHEN AD RISK AND INCIDENCE IS HIGHEST. FEMALE LONGEVITY IN AD IS OBSERVED AROUND THE WORLD. SHOWN HERE ON THE TOP RIGHT GRAPH, YOU CAN SEE THAT AFTER THE ONSET OF AD WOMEN WILL LIVE LONGER, HERE IN RED, COMPARED TO THE MEN, WHO PROGRESS TO DEATH FASTER, HERE IN BLUE. AND THIS PHENOMENON OF FEMALE LONGEVITY EXTENDS TO MANY MOUSE MODELS OF ALZHEIMER'S DISEASE, SEEN HERE ON THE BOTTOM IN THE APPJ20 MODEL. FEMALE APP MICE, HERE IN RED, LIVE LONGER THAN MALE APP MICE WHO PROGRESS TO DEATH FASTER, HERE IN BLUE. NOW, IT'S IMPORTANT TO STUDY FEMALE LONGEVITY AND AD, NOT BECAUSE WE WANT TO LIVE LONGER WITH THE DISEASE, BUT IF WE CAN UNDERSTAND MECHANISMS OF LONGEVITY, THERE IS FERTILE GROUND TO UNRAVEL NEW THERAPEUTIC STRATEGIES TO SUPPORT RESILIENCE IN BOTH SEXES. FEMALES HAVE TWO X CHROMOSOMES, AND IN DEVELOPMENT ONE IS SILENCED THROUGH RANDOM X INACTIVATION. HOWEVER, THIS X IS NOT TOTALLY ASLEEP, AND THERE IS SOME TRANSCRIPTIONAL ESCAPE, BOTH IN THE HUMAN BRAIN AND IN THE MOUSE BRAIN. THERE IS ONE OF A HANDFUL OF FACTORS THAT CONVERGE IN BOTH HUMAN AND MOUSE X CHROMOSOME ESCAPE, AND THAT IS KDM6A. SHOWN HERE ON THE BOTTOM, YOU CAN SEE IN AN X-X MOUSE NEURON, KDM6A IS TRANSCRIBED HERE IN RED, FROM BOTH THE INACTIVE CHROMOSOME AND THE ACTIVE X CHROMOSOME. SO, BOTH X CHROMOSOMES, ACTIVE AND INACTIVE, WILL EXPRESS KDM6A, COMPARED TO A MALE MOUSE NEURON, WHERE IT'S TRANSCRIBED OFF OF THE ONLY ACTIVE X. THIS LEADS TO HIGHER LEVELS OF KDM6A IN X-X BRAINS COMPARED TO X-Y. SO WHAT IS KDM6A? IT'S A HISTONE DEMETHYLASE. IT'S AN EPIGENETIC FACTOR THAT UNWINDS DNA, THE TRANSCRIPTION OF TARGET GENE EXPRESSION. MUTATIONS IN KDM6A LEAD TO SYNDROMES IN HUMANS THAT INVOLVE INTELLECTUAL DISABILITY, AND WE RECENTLY FOUND THAT THERE IS A GENETIC VARIANT OF KDM6A THAT ASSOCIATES WITH HIGHER LEVELS OF THE PROTEIN IN HUMAN BRAINS. SO WE WONDERED WHETHER KDM6A, THE X FACTOR THAT ESCAPES INACTIVATION, COULD CONTRIBUTE RESILIENCE AGAINST ALZHEIMER'S RELATED TOXICITIES. IN OUR PRELIMINARY STUDIES, WE MODULATED KDM6A LEVELS IN MOUSE MODELS. THROUGH AN APPROACH OF GENETIC ENGINEERING, WE RAISED KDM6A LEVELS IN THE MALE APP MOUSE BRAIN IN THE HIPPOCAMPUS, THE LEARNING AND MEMORY CENTER, AND WHEN WE BOOSTED THIS X FACTOR TO FEMALE LEVELS IN THE MALE BRAIN, COGNITIVE DEFICITS IMPROVED, THUS INDUCING A RESILIENCE TO THE SAME AMOUNT OF AMYLOID TOXICITY. WE RELATE OUR MOUSE MODELS TO HUMAN DATA TO INCREASE THE RELEVANCE OF OUR WORK. USING PUBLIC DATABASES, IN THIS CASE THE GTEX PORTAL AND THE ADNI DATABASE, WE FOUND THAT A GENETIC VARIANT OF KDM6A THAT ASSOCIATES WITH HIGHER LEVELS IN THE BRAIN ALSO ASSOCIATES WITH COGNITIVE RESILIENCE. THAT IS, THOSE PEOPLE THAT CARRY TWO COPIES OF THIS GENETIC VARIANT, THOSE PEOPLE WITH HIGHER KDM6A LEVELS IN THEIR BRAIN HERE IN BLUE, DID NOT SHOW COGNITIVE DECLINE IN THE ADNI DATABASE OVER A DECADE. NOW, THIS IS IN CONTRAST TO THOSE PEOPLE WHO DID NOT CARRY THE VARIANT, WITH LOWER LEVELS OF KDM6A, WHO SHOWED SIGNIFICANT COGNITIVE DECLINE OVER A DECADE. THIS GROUP IS ENRICHED FOR INDIVIDUALS WITH MILD COGNITIVE IMPAIRMENT. BUT SHOWS US THAT THERE'S SOME ASSOCIATION OF KDM6A AND RESILIENCE IN HUMANS. WE ARE GRATEFUL TO DELVE INTO THIS AREA DEEPER WITH A GRANT FROM THE NIA TO STUDY SEX DIFFERENCES IN THE X CHROMOSOME AND ALZHEIMER'S DISEASE, AND WE'LL BE SPECIFICALLY STUDYING: ONE, KDM6A AND ITS DISTRIBUTION AND NEURAL RESILIENCE IN X-X COMPARED TO X-Y CELLS; NUMBER TWO, TO REALLY UNDERSTAND HOW IT ACTS IN RESILIENCE TO ALZHEIMER'S DISEASE DEFICITS IN NEURONS AND IN MICE - IS IT THROUGH ACTING AS AN EPIGENETIC FACTOR; AND THREE, WE WILL ASSESS THE GENETIC VARIATION OF KDM6A AND ITS ASSOCIATION WITH AGING AND AD IN MEN COMPARED TO WOMEN. WE ACKNOWLEDGE THE NIH FOR OUR WORK, AS WELL AS THE PUBLIC DATABASES AND RESOURCES THAT ENABLE THIS TRANSLATIONAL APPROACH TO STUDY THE X CHROMOSOME AND SEX DIFFERENCE IN AD, AND WE ARE VERY HOPEFUL AND EXCITED THAT THIS MAY OPEN A NEW AREA TO UNDERSTAND SEX CHROMOSOMES IN ALZHEIMER'S DISEASE AND MAYBE COULD OPEN A THERAPEUTIC PATH TO RESILIENCE IN BOTH MEN AND IN WOMEN. THANK YOU IVAN NALVARTE: SO, HELLO. OUR RESEARCH IS TO UNDERSTAND THE ROLE OF SEX HORMONES AND IN PARTICULAR, THE FEMALE SEX HORMONE ESTROGEN IN NEURODEVELOPMENT AND IN NEUROLOGICAL DISEASES. THE CHIEF FOCUS OF OURS HAS BEEN ALZHEIMER'S DISEASE. IT IS MORE PREVALENT IN WOMEN THAN IN MEN. WOMEN ARE AT AROUND TWO TO THREEFOLD HIGHER RISK OF BEING DIAGNOSED WITH ALZHEIMER DISEASE THAN MEN. THIS COULD TO SOME EXTENT BE DUE TO THE FACT THAT WOMEN, ON MORE AVERAGE, LIVE LONGER THAN MEN, BUT IT IS CLEAR THAT OTHER GENDER AND SEX-BIASED FACTORS AND THE INTERACTION PARTICIPATE IN THIS INCREASED FEMALE RISK. SO, WE STUDY THE CONTRIBUTION OF SEX HORMONES, IN PARTICULAR ESTROGEN, ON AD RISK AND AD PATHOLOGY. IT'S WELL KNOWN THAT SEX HORMONES HAVE NEUROPROTECTIVE PROPERTIES. HOWEVER, THE INTERACTION CONTRIBUTED HERE IS WHERE IT CONFLICTS AND NOT STRAIGHTFORWARD TO STUDY. MANY VARIABLES EXIST THAT MUST BE CONSIDERED, BOTH BIOLOGICAL VARIABLES AND NON-BIOLOGICAL SOCIAL AND ENVIRONMENTAL VARIABLES. ALTHOUGH IT'S QUITE WELL ESTABLISHED THAT EARLY MENOPAUSE IS ASSOCIATED WITH INCREASED RISK OF DEMENTIA, IT'S MORE CONTROVERSIAL IF ESTROGEN HORMONE REPLACEMENT THERAPY AT MENOPAUSE MAY LOWER RISK OF AD AND OTHER DEMENTIAS LATER IN LIFE. THESE CONTROVERSIES ARISE FROM THE LIMITED POPULATION DATA AVAILABLE ON DATED HORMONE REPLACEMENT THERAPY YEARS THAT CAN BE FOLLOWED UP REGARDING AD AND OTHER DEMENTIA OUTCOME. IN ADDITION, THE CONTRIBUTION OF SPECIFIC SEX HORMONE RECEPTOR AND THE ISOFORM NEUROPROTECTION IS STILL LARGELY UNKNOWN. SO, IN MY LAB, WE WANT TO ADDRESS THESE ISSUES, FIRSTLY BY USING COHORT DATA ON HORMONE REPLACEMENT THERAPY YEARS, AND SECONDLY BY MODELING MENOPAUSE AND ESTROGEN THERAPY IN MOUSE MODELS OF AD. THE COHORT DATA CONSISTS OF OVER 88,000 SWEDISH POST-MENOPAUSAL WOMEN WITH DETAILED INFORMATION ON THEIR HORMONE REPLACEMENT THERAPY YEARS. THIS DATA INCLUDE TYPE OF -- TYPE ROUTE OF ADMINISTRATION, TIME OF INITIATION, AND DURATION OF HORMONAL THERAPY. WE ALSO HAVE DETAILED INFORMATION ON IMPORTANT CONFOUNDING VARIABLES THAT MUST BE ACCOUNTED FOR, SUCH AS EDUCATION, BMI, AGE AT MENOPAUSE ONSET, PARITY, CONTRACEPTIVE USE, AS WELL AS CARDIOMETABOLIC DISEASE. MANY OF THESE FACTORS DON'T ONLY INTERACT WITH AD RISK, BUT ALSO WITH ESTROGEN SIGNALING. IN ADDITION, WE HAVE GENETIC DATA MOST PARTICIPANTS, WHICH MEANS THAT WE CAN STUDY GENETIC INTERACTIONS, WHICH ONE OBVIOUS INTO STUDY IS APO-E. THE INDIVIDUALS ARE FOLLOWED OVER TIME, AND INFORMATION AND THE INCIDENCE IS EXTRACTED FROM SWEDISH NATIONAL REGISTERS ON INPATIENT CARE AND CAUSE OF DEATH. IN ADDITION, WE HAVE -- WE CAN GET OUTPATIENT DATA FROM -- ON BOTH AD AND NON-AD DEMENTIA OUTCOME FROM SWEDISH QUALITY -- FROM A SWEDISH QUALITY REGISTER CALLED SWEDEM. THIS MEANS THAT WE WILL HAVE UNIQUE COVERAGE AND DETAIL IN OUR POPULATION DATA THAT WE CAN -- WE HOPE WILL BE A SPRINGBOARD TO PROVIDE MORE CONCLUSIVE ANSWERS TO QUESTIONS SUCH AS IF AGE AT MENOPAUSE CAN BE A RISK FACTOR FR AD AND IF ESTROGEN THERAPY CAN MODULATE THAT RISK. AND IN SUCH CASE, WHEN SHOULD WE INITIATE IT AND FOR HOW LONG? WE ALSO WANT TO LINK THE DATA ACQUIRED IN THE COHORTS TO EXPERIMENTAL DATA WHERE WE ALREADY NOW SEE THAT SURGICAL REMOVAL OF THE OVARIES, SO-CALLED OVARIECTOMY, WORSENS PATHOLOGY IN SPECIFIC BRAIN REGIONS IN THE MOUSE MODEL FOR AD, THE APP-NLGF MOUSE. AND THE SELECTIVE AGONISTS FOR ESTROGEN RECEPTOR BETA, OR ER BETA, APPEARS TO BE NEUROPROTECTIVE. AND WE THINK THAT ER BETA MODULATION MIGHT BE EXPLAINING KEY ROLE IN THIS NEUROPROTECTION. WE ARE, OF COURSE, NOW FOLLOWING UP WITH THESE FOR EXCITED DATA ONLY SINCE ER BETA SELECTIVE AGONISTS HAVE KNOWN ADVERSE SIDE EFFECTS DESCRIBED FOR E ALPHA ACTIVATION. SO, WITH THE SUPPORT FROM NIA, WE HAVE NOW THE POSSIBILITY TO, FOR THE FIRST TIME, BRING CONCLUSIVE DATA ON THE EFFECT OF MENOPAUSE AND HORMONE REPLACEMENT THERAPY ON BOTH AD AND NON-AD DEMENTIA RISK. THIS IS THE COHORT DATA. IT IS VERY DETAILED. YOU CAN UTILIZE THIS DETAIL IN INTEGRATION WITH EXPERIMENTAL MODELS FOR AD AND MENOPAUSE. THIS WILL HELP US IN UNDERSTANDING THE MOLECULAR UNDERPINNINGS OF SEX HORMONE -- SEX HORMONAL NEUROPROTECTION WHERE, AS I JUST MENTIONED, ER BETA APPEARS TO BE OF SPECIAL INTEREST. WE ALSO WANT TO VERIFY KEY SEX HORMONE-REGULATED PATHWAYS AND GENES THAT ARE IDENTIFIED IN THE MODELS AGAINST HUMAN BRAIN BANK -- BRAIN BANK DATA. HERE, THE RUSH AD RESEARCH CENTER BRAIN BANK WOULD BE A VALUABLE RESOURCE WITH ITS DETAILED PATIENT SAMPLE INFORMATION, WHICH INCLUDES, FOR EXAMPLE, WOMEN WITH HISTORY OF HORMONE REPLACEMENT THERAPY YEARS, AS WELL AS EARLY RISK FACTORS SUCH AS CARDIOMETABOLIC DISEASE. USING THIS MULTIDISCIPLINARY AND INTEGRATIVE APPROACH, WE HOPE THAT WE WOULD BE ABLE TO NOT ONLY VALIDATE THE OTHER DATA, BUT ALSO IDENTIFY THE EXTENT OF ESTROGENIC CONTRIBUTION TO NEUROPROTECTION, AS WELL AS THE UNDERLYING MOLECULAR DETERMINANTS BEHIND THIS NEUROPROTECTION. SO WE HOPE THAT SUCH UNDERSTANDING CAN IDENTIFY NEW AD RISK FACTORS AND PROMOTE NEW, MORE PERSONALIZED RECOMMENDATIONS GIVEN TO BOTH WOMEN AND MEN, AS WELL AS IDENTIFY THE CLINICAL POTENTIAL OF ER BETA. GUOJUN BU HELLO. THE TITLE OF MY TALK TODAY IS "INTERACTIONS BETWEEN APOE, SEX, AND AGING IN ALZHEIMER'S DISEASE: IMPLICATIONS ON TARGETING STRATEGIES". THIS WORK IS SUPPORTED BY A M2OVE-AD CONSORTIUM GRANT AND ALSO A GRANT AT APOE2. SO, MY LAB HAS BEEN INTERESTED IN STUDYING THE EFFECT OF APOE GENOTYPE, AGE, AND SEX, THREE STRONG RISK FACTORS FOR ALZHEIMER'S DISEASE. THE MOLECULAR PATHWAYS, USING MULTI-OMIC APPROACH -- SO, FOR THIS STUDY WE USE HUMANIZED APOE ANIMALS EXPRESSING E2, E3, AND E4, AND THEN AT THE YOUNG AGE, MIDDLE, OR OLD AGE RISK WE EXPOSE MALE AND FEMALE ANIMALS. SO, FOR ALL THE MULTI-OMIC STUDIES WE PERFORMED TRANSCRIPTOMIC STUDIES THROUGH BULK RNASEQ OR SINGLE CELL RNASEQ. WE ALSO PERFORMED PROTEOMIC, METABOLOMIC, AND LIPIDOMIC, WITH EITHER BRAINS AND/OR SERUM SAMPLE. SO, ALL THE DATA AS THEY GENERATE, HAVE OR WILL BE DEPOSIT AT THE AD KNOWLEDGE PORTAL DATA DEPOSIT SITE. IN THIS PAPER WE PUBLISH LAST YEAR, NEURON, WE REPORTED THE DATA FROM TRANSCRIPTOMIC STUDY AND BULK RNASEQ LEVEL FROM BRAIN SAMPLE AND ALSO THE SERUM METABOLOMIC. WHAT WE FOUND WAS THAT APOE GENOTYPE HAS A STRONG EFFECT IN PARTICULAR IF APOE4 UP-REGULATE SERPINA3N, WHICH IS A MEMBER A SERINE-TYPE ENDOPEPTIDASE INHIBITOR FAMILY. APOE2 UP-REGULATES SEVERAL KEY METABOLITES IN THE SERUM. FOR AGE-DEPENDENT EFFECT, WE SAW UP-REGULATION OF IMMUNE RESPONSE MODULE, ALSO EXTRACELLULAR VESICLE PATHWAY, BUT THE SYNAPTIC TRANSMISSION PATHWAY IS DOWN-REGULATED. FOR SEX-DEPENDENT EFFECTS, WE SAW IN THE FEMALES, THERE'S AN UP-REGULATION BEHAVIOR/NEUROLOGICAL SYSTEM, ALSO IMPLICATION OF LONG-TERM DEPRESSION. SO, WE THEN PERFORMED THE SINGLE CELL RNA SEQUENCING USING THE SAME ANIMAL MODELS, AND THIS IS THROUGH 10X GENOMIC PLATFORM. SO, AS YOU CAN SEE THAT IN THIS WORK WE FOUND -- IDENTIFIED 24 CELL CLUSTERS. THERE ARE MICROGLIA, NEURONS, ASTROCYTES, OLIGODENDROCYTE, AND VASCULAR CELLS. SO, WHAT WE FOUND WAS THAT AGING HAS A STRONG EFFECT ON THE MICROGLIA CELL CLUSTERS, SO ALL OF THESE EIGHT CELL -- MICROGLIAL CLUSTERS HAVE SIGNIFICANT UP-REGULATED OR DOWN-REGULATED DIFFERENTIAL EXPRESSION, AND FOLLOWED BY THE EFFECT OF SEX, AND NOW APOE GENE TYPE. IF WE LOOK AT THE SPECIFIC GENES, WE SAW THAT GENES ASSOCIATED WITH MICROGLIAL ACTIVATION, SUCH AS APOE, ARE SIGNIFICANTLY UP-REGULATED AS A FUNCTION OF AGING. COMPARING AT 24 MONTHS, THREE MONTHS. WHEREAS GENES ASSOCIATED WITH HOMEOSTATIS [SPELLED PHONETICALLY] -- THE STATUS OF MICROGLIA, SUCH AS TMEM119, ARE DOWN-REGULATED. SO, THIS SIGNATURE OF MICROGLIA EARLY RESEMBLES WHAT WE SAW -- HOW MICROGLIA RESPOND TO AMYLOIDS, KEY PATHOLOGY FOR ALZHEIMER'S DISEASE. SO, THOSE MICROGLIA ARE CALLED DISEASE-ASSOCIATED MICROGLIA OR DAM. IN TERMS OF PATHWAY, THE STRESS-RELATED PATHWAY SUCH AS EIF2 SIGNAL PATHWAY ARE UP-REGULATED BY AGING, WHEREAS SURVIVAL OR METABOLISM-RELATED PATHWAYS, SUCH AS MTORS ARE DOWN-REGULATED. THE APOE GENOME HIGHLY EFFECT IS SEEN PARTICULAR IN THE AGED ANIMAL, WITH E2 HAS A STRONGEST EFFECT. WE ALSO SAW THE EFFECT IN ASTROCYTES, SO, SPECIFICALLY AGING ACTUALLY DOWN-REGULATED ASTROCYTE CELL NUMBER IN THESE THREE CELL CLUSTERS, CLUSTERS ZERO, FIVE, AND 23. BUT INTERESTINGLY, WE SAW THE SEX HAS THE BIGGEST EFFECT ON THE DEGS, IN PARTICULAR FEMALE HAS VASTLY DOWN-REGULATED THE EGES IN CLUSTER FIVE, WHICH IS APOE NEGATIVE, AND THIS IS AGE INDEPENDENT. SOME OF THESE PATHWAYS, SUCH AS EIF2 SIGNALING, MTOR PATHWAYS ARE DOWNREGULATED. SOME OF THE KEY GENES ASSOCIATED WITH ASTROCYTE FUNCTION, SUCH AS CLU THROUGH AQUAPORIN 4 IS ALSO DOWNREGULATED IN FEMALES. SO, WE'RE CURRENTLY VALIDATING SOME OF THESE FINDINGS, BOTH AT THE GENE EXPRESSION LEVEL AND ALSO AT THE FUNCTION LEVEL. WE'RE ALSO PERFORMING PARALLEL STUDY USING SINGLE CELL APPROACHES USING HUMAN POST-MORTEM BRAIN. SO, WE THINK -- WE'RE ALREADY STUDYING THE COLLECTIVE EFFECT, OR INDIVIDUAL EFFECT, IN THEIR ACTING EFFECT OF AGING SEX AND APOE GENOTYPE CAN HELP US IDENTIFY MOLECULAR PATHWAY IN PARTICULAR THE SPECIFIC TARGET TO DESIGN NOVEL THERAPY FOR ALZHEIMER'S DISEASE. THANK YOU. BEFORE I DO THAT I WANT TO THANK THE ORGANIZERS FOR GIVING ME THE OPPORTUNITY TO PREPT OUR WORK HERE AND THEN I OF COURSE, HAVE ALSO TO MENTION, I'M GOING TO PRESENT IS REALLY A RECITE OF AN EFFORT OF MANY SCIENTISTS BROUGHT TOGETHER AS WELL AS PARTNERS AND ASSOCIATED CONSORTIA. I HAVE TO ACKNOWLEDGE THE SIGNIFICANT FUNDING FROM N.I.A. WHICH ENABLES OUR RESEARCH. BEFORE I GO INTO SOME OF OUR DISCOVERIES IN MORE DETAIL, I WANT TO GIVE A BRIEF OVERVIEW OF THE RESOURCES WE WERE ABLE TO GENERATE FOR THE INITIATIVE IN THE PROJECTS. OUR CONSORTIUM IS USING READ OUT FOR HEALTHY AGING AS WELL AS PATHOGENIC PROCESSES. IN ORDER TO DO SO WE HAVE GENERATED BROAD PROFILING AROUND 50,000 SAMPLES. MOST OF THESE PROFILES ARE FROM HUMAN BLOOD BUT MORE RECENTLY WE TURN TO METABOLIC PROFILING OF BRAIN TISSUE. IN ADDITION TO OUR STUDIES, WE ARE WORKING WITH THE MODEL A.D. CONSORTIUM AND OTHER PARTNERS TO TRANSLATE OUR FINDINGS FOR RELEVANT MOUSE FODELS. WE HAVE PUT A LOT OF EFFORT IN TECHNICAL STANDARDIZATION AND DEVELOPMENT OF QUALITY CONTROL PIPELINES FOR OUR DATA SETS. LINK THAT COMBINES METABOLIMICS. USING THIS DATA, WE HAVE COMPILED A LARGE COLLECTION OF METABOLIC CHANGES THAT SERVE IN ALZHEIMER'S DISEASE. ON THE LEFT I'M SHOWING A NON-COMPREHENSIVE LISTING OF SOME OF OUR STUDIS TO DEMONSTRATE BROAD ASSOCIATION OF CHANGES IN THE BLOOD AND ITS MARKERS AND USING ASSETS AS A READ OUT OF GUT MICROBIOME, POTENTIAL RISK FACTOR FOR ALZHEIMER'S DISEASE. TURNING AWAY FROM THESE ASSOCIATION ANALYSES, ON THE RIGHT I'M SHOWING SOME RESULT STUDY WHERE WE INVESTIGATED MODULATED WITH A.D. BIO MARKERS ACROSS MEASURES THROUGH 2AD RISK FACTORS NAMELY SEX AND APOE. TWO OUTCOMES WERE FIRST THAT ASSOCIATION OF COMPLEX LIPIDS WITH A.D. PATHOLOGY WERE SIGNIFICANTLY STRONGER IN APOE CARRIERS AND SECOND EFFECTS METABOLITES LINKED TO MIGHT MITOCHONDRIA -- TO EXPLORE THESE FINDINGS FURTHER ON THE ONE HAND WE LOOKED AT THE EFFECTS OF APOE2 AND 4 IN HEALTHY INDIVIDUALS. THERE WE OBSERVED ASSOCIATION LIPID WITH AE04 AND INVERSE ASSOCIATIONS. A SIGNIFICANT AMOUNT OF THE EFFECTS OF APOE4 AND PROTECTIVE EFFECTS OF E2 ARE ACTUALLY MEDIATED BY THE ASSOCIATED SPECIES. THE OTHER HAND WE FURTHER INVESTIGATED PROFILES IN ALZHEIMER'S DISEASE AND HERE, WE FOUND THIS IDENTIFY CLINICALLY DIFFERENT SUBGROUPS USING UNSUPERVISED CLUSTERING OF PROFILES OF METABOLITES CENTRALLY INVOLVED IN ENERGY METABOLISM. IMPORTANTLY THIS APPROACH DETECTED NOT ONLY GROUPS MORE PROGRESSED IN DISEASE BUT ALSO RESILIENCE WITH INDIVIDUALS NO EVIDENCE OF A.D. PATHOLOGY. NOW OF COURSE, WE WILL NEED TO REPLICATE THESE FINDINGS IN INDEPENDENT STUDIES. HOWEVER, METABOLIC CONSTITUTE RISK FACTORS. THAT MEANS THAT IF OUR FINDINGS SHOULD HOLD, THEY PROVIDE US WITH SEVERAL LEADS FOR NON-INVASIVE PREVENTIVE TOOLS, LIFESTYLE ADJUSTMENTS OR SUPPLEMENTATION THAT COULD BE EVALUATED FURTHER. WITH THAT I WOULD LIKE TO THANK YOU FOR LISTENING AND HOPE YOU ENJOY THE REST OF THE SUMMIT. AS MOST OF YOU KNOW, AGING IS ACTUALLY THE LARGEST RISK FACTOR FOR ALZHEIMER'S DISEASE AND THE RISK INCREASES EXPONENTIALLY AS A FUNCTION OF AGE. WHAT MY LAB IS REALLY INTERESTED IN, THE RATE WHICH PEOPLE ARE ACTUALLY AGING WHEN WE TALK ABOUT BUY -- BIOLOGICAL, WHETHER THAT DIFFERENTIATES THE RISK. AND MORE PART OF THE RESILIENCE CONSORTIUM FROM N.I.A., WE ARE ACTUALLY INTERESTED IN STUDYING AMONG SUSS SUSCEPTIBLE PEOPLE WHETHER AGING IS MODULATING THE RISK. WE ARE LOOKING AT INDIVIDUALS WITH APOE4. USING THE COHORT, WE ENRICHED SAMPLE FOR APOE4 AND E4 AND E34. AND ON THESE INDIVIDUALS WE HAVE 350 SAMPLES WHERE WE GENERATED BOTH DNA METHYLATION DATA. SEQUENCING DATA AND WE HAVE DONE THIS ON THREE DIFFERENT BRAIN REGIONS FROM INDIVIDUALS -- WHAT MY LAB IS DOING, USING BIO INFORMATICS TECHNIQUES TO COMBINE THIS DATA TO UNDERSTAND EITHER RESILIENCE OR SUSCEPTIBILITY TO ALZHEIMER'S DISEASE AMONG THESE GENETICALLY PREDISPOSED INDIVIDUALS, FOCUSED ON STUDYING FROM AN AGING PERSPECTIVE. WE ARE UPLOADING THE DNA METHYLATION DATA AND THE OTHER DATA WILL BE AVAILABLE AS WELL. SO JUST BRIEFLY TO DESCRIBE A LITTLE BIT OF WHAT WE HAVE DONE SO FAR. MY LAB DOES A LOT IN WORKING WITH WHAT ARE CALLED EPIGENETIC CLOCKS. YOU CAN TAKE DNA METHYLATION LEVELS ACROSS THE GENOME AND COMBINE TO GET A PREDICTED EPIGENETIC AGE FOR AN INDIVIDUAL. WE HAVE DONE THIS IN THE DORSAL PREFRONTAL CORTEX, AS WELL AS A FEW OTHER BRAIN BIO BANKS AND WE GENERATED THIS EPIGENETIC AGE, WHICH IF YOU LOOK ON THAT X AXIS WE PLOTTED AGAINST CHRONOLOGICAL AGE AND GET A VERY GOOD PREDICTOR OF AGE. BUT MUCH MORE IMPORTANTLY THAN GETTING THE PREDICTOR OF AGE IS WHETHER THE DISCORDANCE, WHETHER SOMEONE PREDICTED OLDER OR YOUNGER THAN THEY ACTUALLY ARE, HAS SOME BEARING ON NEURO DEGENERATION. WHAT WE ACTUALLY FIND IS THAT, THIS RESIDUAL IS ASSOCIATED WITH BOTH COGNITIVE DIAGNOSIS OF A.D. AS WELL AS NEURO PATHOLOGICAL DIAGNOSIS OF A.D., INTERESTINGLY IT SEEMS TO BE ACCELERATED IN INDIVIDUALS WITH APOE E4. THE OTHER THING WE'RE ACTUALLY REALLY INTERESTED IN DOING IS ASKING WHETHER WE CAN ACTUALLY CAPTURE THESE SAME SIGNATURES OR SAME CHANGES WHEN LOOKING AT IN-VITRO CELL CULTURE. SO, IT'S REALLY DIFFICULT TO STUDY THE PROGRESSION -- AT LEAST FROM AN AGING PERSPECTIVE -- OF THESE CHANGES IN BRAIN, BECAUSE WE USUALLY REQUIRE POST-MORTEM BRAIN SAMPLES. SO, MY LAB'S ACTUALLY ASKED IF WE CAN AGE CELLS IN-VITRO TO MIMIC THESE SAME CHANGES; AND FROM THERE, WE CAN ACTUALLY MODULATE AND STUDY MORE MECHANISTICALLY WHAT'S GOING ON. SO, WHAT WE'VE DONE IS WE'VE ACTUALLY AGED ASTROCYTES IN CULTURE AND DEVELOPED A VERY SIMILAR KIND OF EPIGENETIC AGING MEASURE, THIS TIME AS A FUNCTION OF DAYS IN CULTURE. SO, THIS IS FROM OUR TRAINING SAMPLE. THIS IS FROM OUR VALIDATION SAMPLE FOR THE IN-VITRO CULTURE. BUT MORE EXCITINGLY, WHAT WE'VE DONE IS WE'VE THEN GONE BACK AND APPLIED THIS TO THE ROSMAP COHORT, WHICH IS, AGAIN, BULK BRAIN DATA. WE FIND THAT THIS SCORE ACTUALLY TRACKS WITH AGING. BUT AGAIN, MORE IMPORTANTLY, THE RESIDUALS -- SO, WHETHER SOMEONE HAS A HIGHER SCORE OR LOWER BASED ON WHAT WE'D EXPECT FOR THEIR AGE IS REFLECTED IN THE DIFFERENTIAL NEUROFIBRILLARY TANGLES AND NERITIC PLAQUES. SO, WE REALLY THINK THAT, GOING FORWARD, USING A MODEL LIKE THIS WILL ACTUALLY ENABLE US TO BETTER UNDERSTAND MECHANISM AND ACTUALLY MANIPULATE THE SYSTEM TO DETERMINE, ACTUALLY, WHAT'S MODULATING RISK OF THESE -- FOR THESE INDIVIDUALS.THANK YOU VERY MUCH. [END OF TRANSCRIPT] I WILL BE TALKING ABOUT SERUM PROTEOME ANALYSIS OF ALZHEIMERÍS DISEASE IN THE AGES STUDY. THE AGES PARTICIPANTS ARE BORN BETWEEN 1907 AND 35. MEN AND WOMEN, IN ICELAND. IT RECRUITED INTO THE REYKJAVIK STUDY IN 1967, REPEATED VISITS AND AGES VISITS STARTED IN 2002. AND IT REPEATED FIVE YEARS LATER. AND IT HAS EXTREMELY DEEP PHENOTYPING INCLUDED IN MRI IMAGES OF THE BRAIN, WHICH WE HAD PROCESSED INTO 58 REGIONAL VOLUMES, AND DONE TISSUE CLASSIFICATION.WE ALSO HAVE LONGITUDINAL INFORMATION ON, SAY, VOLUMES, AND WE CAN SEE DIFFERENCES BETWEEN THOSE WITH DISEASE AND NOT WITH DISEASE. IN OFFICIAL, WE HAVE SO MUCH DONE OF NEARLY 4800 SERUM PROTEINS FOR NEARLY 5500 INDIVIDUALS, REPEATED A LOT OF THEM IN FIVE YEARS TIME, FIVE YEARS LATER. AND WE HAVE A PROTEIN GWAS, AND OTHER GWASS AND OTHER GENETIC INFORMATION.WHAT WE WILL BE DESCRIBING HERE IS A COMPARISON OF THE DEEP BLOOD AND BRAIN PROTEOME. WE PUBLISHED TWO YEARS BACK A PAPER ON THE EXAMINATION OF 5782 SERUM PROTEINS IN THE AGES POPULATION. PROTEINS CLUSTERED INTO 27 MODULES, WHICH WERE UNDER GENETIC CONTROL AND ASSOCIATED WITH VARIOUS DIFFERENT DISEASES.FOR COMPARISON, WE DRAW ON THIS PAPER PUBLISHED LAST YEAR BY THE EMORY GROUP, SHOWING 3500 PROTEINS IN AD CSF AND 12,000 IN BRAIN. WHEN WE LOOK SPECIFICALLY AT THESE CSF PROTEINS, AND COMPARE THAT TO OUR OWN SERUM PROTEOME, WE CAN SEE THAT WE HAVE 52 PERCENT OF THE CSF PROTEINS IN OUR PANEL.WHEN WE LOOK AT THAT WITH RESPECT TO THE MODULES, WE CAN SEE THAT WE HAVE AT LEAST FIVE MODULES, THREE OF WHICH ARE ASSOCIATED WITH ALZHEIMERÍS DISEASE. ONE, THIS ONE HERE, 27, IS OF PARTICULAR INTEREST TO US. IT HAS AN IKEN [SPELLED OR THE FIRST PRINCIPAL COMPONENT THAT IS ASSOCIATED WITH INCIDENT ALZHEIMERÍS DISEASE. IN IT ARE 378 PROTEINS, AND 63 PERCENT OF THEM ARE ALSO FOUND IN CSF. AND WHEN WE GO OVER HERE, THATÍS 239 PROTEINS, AND THATÍS A VERY HIGHLY ENRICHED AND HIGHLY SIGNIFICANTLY ENRICHED. ONE OF THE THINGS THAT IS DESCRIBED IN THE EMORY PAPER, OR THE HIGGINBOTHAM PAPER, IS THEY IDENTIFY 528 DIFFERENTIALLY EXPRESSED CSF PROTEINS IN ALZHEIMERÍS PATIENTS, AND IF WE LOOK AT THOSE PROTEINS AND PROTEIN MODULE 27, WE CAN SEE THAT THERE ARE 53 OF THEM THAT ARE COMMON.SO, TAKEN TOGETHER THESE FINDINGS PROVIDE NEW OPPORTUNITIES FOR UNDERSTANDING THE CROSS-PATH BETWEEN THE BLOOD AND THE BRAIN IN RELATION TO AT. SO WHAT WE ARE WORKING ON NOW IS EXAMINING LOAD USING HIGH-DIMENSIONAL DATA ACROSS POPULATIONS. WE ARE THROWING ON THE AGES REYKJAVIK STUDY WITH A NUMBER OF BOTH PREVALENT AND INCIDENT AD CASES. THROWING ON THE PHENOTYPES INCLUDING THE REGIONAL VOLUMES, THE SERUM PROTEINS AND NETWORKS THAT I JUST TALKED ABOUT. WE HAVE THE GENOMICS. AND THEN WHAT I TALKED ABOUT, THE CSF AND BRAIN PROTEOMES.AND WE ARE COLLABORATING WITH THE EMORY GROUP, LEVERAGING ON THE AMP-AD DATASET IN AN INTEGRATIVE ANALYSIS, HOPING TO CAST LIGHT ON NEW MECHANISTIC INSIGHTS, MANY DEFINED CAUSAL TARGETS, LONGITUDINAL CHANGES, BIOMARKERS. AND THIS IS ALL A PART OF OUR NIA GRANT. THANK YOU. HELLO, IT'S MY GREAT PLEASURE TO PRESENT ON THIS MEETING TODAY. NEUROPSYCHIATRIC SYMPTOMS ARE CORE FEATURES OF ALZHEIMER'S DISEASE, AND THEY ARE ASSOCIATED WITH MAJOR ADVERSE AFFECTS OF DAILY FUNCTION AND QUALITY OF LIFE, AND WITH WORSE DISEASE PROGNOSIS. NEUROPSYCHIATRIC SYMPTOMS IN AD SHARE SOME CLINICAL FEATURES WITH SERIOUS MENTAL ILLNESS, BUT WHETHER THESE CONDITIONS SHARE SIMILAR IDIOPATHIES IS UNCLEAR. GIVEN THAT RELIABLE TREATMENTS FOR NEUROPSYCHIATRIC SYMPTOMS IN THE CONTEXT OF ALZHEIMER'S DISEASE AND OTHER DEMENTIAS DO NOT EXIST, THIS PSYCH AD CONSORTIUM WAS ESTABLISHED TO IDENTIFY RELIABLE BIOMARKERS THAT COULD LEAD TO NOVEL THERAPEUTICS.THE OVERARCHING GOALS OF OUR PSYCH AD PROPOSAL IS TO BETTER UNDERSTAND THE SHARED AND DISTINCT MOLECULAR MECHANICS AND PATHWAYS UNDERLYING NEUROPSYCHIATRIC SYMPTOMS IN AD AND OTHER NEUROPSYCHIATRIC ILLNESSES. MORE SPECIFICALLY, WE PROPOSE TO BUILD INTEGRATIVE MODELS USING MULTISCALE DATA FROM MORE THAN 1,700 AUTOPSY CASES. FROM EACH CASE WE INCLUDE PHENOMICS DATA FOR NEUROPSYCHIATRIC SYMPTOMS, DEMENTIA SEVERITY, AND CLINICAL DIAGNOSIS. WE ALSO UTILIZE ARTIFICIAL INTELLIGENCE APPROACHES TO PERFORM DIGITAL PATHOLOGY, AND WE APPLY INNOVATIVE APPROACHES THAT REDUCE THE COST AND TECHNICAL BIASES TO CAPTURE GENE EXPRESSION AND EPIGENETIC REGULATORY ELEMENTS AT THE SINGLE CELL LEVEL.WE EXPECT THAT THESE MODELS WILL ENABLE US TO ASSIGN GENOTYPES AND MOLECULAR MARKERS TO SPECIFIC NEUROPSYCHIATRIC SYMPTOMS WITHIN AD AND OTHER NEUROPSYCHIATRIC TRAITS OF THE SINGLE CELL LEVEL. IN ADDITION, WE WILL TEST THE TRANSLATIONAL POTENTIAL OF THE GENOTYPE MARKER, PHENOTYPE MODELS TO BETTER PREDICT THE NEUROPSYCHIATRIC SYMPTOMS IN AD USING INDEPENDENT LARGE SCALE BIOBANK DATA SETS. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL IDENTIFY SHARED AND DISTINCT MOLECULAR MECHANICS AND NEUROPATHOLOGICAL STAGES THAT ARE ASSOCIATED WITH THE PRESENCE OF NPS IN PATIENTS WITH AD AND SERIOUS MENTAL ILLNESS.MICROGLIA HAS EMERGED AS A CRUCIAL PLAYER IN AD PATHOGENESIS. THIS IS SUPPORTED THROUGH GENETIC ASSOCIATION STUDIES WHERE MANY OF THE COMMON AND RARE RISK LOCI AFFECTING FOR THE PREFERENTIALLY OR SELECTIVELY EXPRESSED IN HBIC, EMPHASIZING THE IMPORTANT ROLE OF THE INNATE IMMUNE SYSTEM IN AD IT IS UNCLEAR IF MICROGLIA ASSUME SOME PROTECTIVE OR DAMAGING ROLE, AND THAT MAY VARY DEPENDING ON THE STAGE AND PROGRESSION OF AD. THEREFORE, FURTHER ANALYSIS OF MICROGLIA AND OTHER IMMUNE CELLS PURIFIED FROM HUMAN BRAIN IS NEEDED. ASSUME A BRAIN'S IMMUNE CELLS; CONSIDER THE SMALL PROPORTION OF TOTAL BRAIN CELLS, HOMOGENY-BASED STUDY IN HUMAN BRAIN TISSUE ARE UNLIKELY TO CAPTURE THE FULL SPECTRUM OF HUMAN BRAIN IMMUNE CELL MOLECULAR SIGNATURES, ESPECIALLY IN LIGHT OF THE GROWING APPRECIATION FOR THE DIVERSITY OF HUMAN BRAIN IMMUNE CELLS IN THE BRAIN.THE PROPOSED STUDIES ADDRESS SOME OF THE LIMITATION OF PREVIOUS RESEARCH AND APPLY INNOVATIVE GENOMIC APPROACHES TO GENERATE MULTI-OMICS DATA FROM HUMAN BRAIN IMMUNE CELLS ISOLATED FROM 500 DONORS INCLUDING WHOLE-GENOME SEQUENCING, RNASEQ, ATAXIC [SPELLED PHONETICALLY], HIGH SEQ CHROMOSOME CONFORMATION CAPTURE, AND PROTEOMICS. SECOND, WE WILL PERFORM STATE OF THE ART SINGLE CELL ANALYSIS THAT WILL ALLOW US TO ACCESS THE DIVERSITY OF HUMAN BRAIN IMMUNE CELL CIRCULATION, AS WELL AS DETECT THOSE THAT ARE ASSOCIATED WITH AD. THIRD, WE WILL CONNECT THE AD RISK LOCI WITH CHANGES IN THE REGULATORY MECHANICS OF GENE AND PROTEIN EXPRESSION IN HUMAN BRAIN IMMUNE CELLS. AND FINALLY, WE'RE GOING TO ORGANIZE THE HUMAN BRAIN IMMUNE CELL MULTISCALE DATA INTO FUNCTIONAL NETWORKS AND IDENTIFY KEY DRIVERS FOR AD.SUCCESSFUL COMPLETION OF OUR PROPOSED STUDIES WOULD PROVIDE AN INCREASED MECHANISTIC UNDERSTANDING OF DYSFUNCTION IN AD RISK LOCI, IT WILL ALSO PRIORITIZE SIGNIFICANT LOCI OF GENES FOR FUTURE MECHANISTIC STUDIES, AND FINALLY WILL GIVE A LARGE SCALE MULTI-DIMENSIONAL DATASET TOGETHER WITH SYSTEM LEVEL ANALYSIS OF THIS DATASET FOR TRANSCRIPTION REGULATION AND HUMAN BRAIN IMMUNE CELLS TO THE SCIENTIFIC COMMUNITY WHICH IS A RESOURCE THAT'S REALLY NEEDED RIGHT NOW. BASED ON INITIAL ANALYSIS OF SINGLE CELL RNASEQ ASSAYS, IMMUNE CELLS FROM BRAIN AND PERIPHERAL BLOOD, WE HAVE DERIVED A PROPOSED AD MODEL WITH POSSIBLE IMPACTS OF DIRECT OR INDIRECT INFLUENTIAL FACTORS AND FUNCTIONAL CHARACTERIZATION OF POPULATION DURING THE PROGRESSION OF AD.CHRONIC INFLAMMATION WITH PRO-SENESCENT FACTORS MAY CONTRIBUTE TO PRE-CLINICAL PATHOGENESIS, LIKE EMULATION OF WHICH MAY INDUCE AGING-RELATED IMMUNO-SENESCENCE. IN RESPONSE TO THE ALTERED INTERNAL AND EXTERNAL MILIEU, PRIMARY MICROGLIA DIFFERENTIATED INTO SPECIALIZED HOMEOSTATIC AND DEGENERATING MICROGLIA STATES. NOW, SELECTED PERIPHERY IMMUNE CELLS CAN BE FURTHER INTEGRATED THROUGH COMPROMISED BLOOD-BRAIN BARRIER TO SUPPORT MICROGLIA PHAGOCYTOSIS AND APOPTOSIS OF INTERFERON NEURONS. AND SPECIFICALLY, WHEN THEY DEFY TO THOSE MICROGLIA STATE CALLED C5 AND C10, WHICH SEEMS TO BE PRESENT IN VARY ADVANCED AD STAGES.NOW, AS A SECOND STEP WE ALSO PERFORM AN ADDITIONAL PRIORITIZATION OF THE TRAIT-ASSOCIATED CELL POPULATION AND GENE BRAIN DISEASES. PATIENT REGRESSION BASE POLYGENIC MODELS THAT WE INCORPORATE USING GWAS SUMMARY STATISTICS FOR AD. DURING THIS ANALYSIS WE WERE ABLE TO IDENTIFY THAT THE SUBPOPULATION C10 OF MICROGLIA CELLS STATE SEEMS TO BE HAVING A ROLE OF BEING A DRIVER FOR AD PATHOGENESIS. OVERALL, THE STUDY EXPLORE THE ASSOCIATION OF MICROGLIA HETEROGENEITY IN THE CONTEXT OF AD UTILIZING THE HUMAN BRAIN TISSUE. THANK YOU SO MUCH FOR YOUR ATTENTION. SO, IN THIS LIGHTNING TALK I'M GOING TO BE DISCUSSING HOW I CAN INTEGRATE ACROSS MULTIPLE STUDIES TO ACTUALLY ENHANCE OUR KNOWLEDGE OF POTENTIAL CANDIDATE CELL TYPES FOR TARGETING. AND SO, THE IDEA HERE IS, AS YOU'VE HEARD FROM MANY OTHER TALKS, BOTH IN THE LONG FORM AS WELL THE LIGHTNING ROUND, THAT THERE ARE MULTIPLE SINGLE NUCLEUS RNA SEQUENCING STUDIES, BOTH COMPLETED AND ALREADY ONGOING, IN TERMS OF TRYING TO IDENTIFY CELL TYPE RESOLUTION CHANGES IN THE PROGRESSION AND ONSET OF ALZHEIMER'S DISEASE.SO, HERE WHAT I'LL BE DISCUSSING IS REALLY TAKING THREE DIFFERENT STUDIES, ALL OF WHICH ARE DEPOSITED IN THE AMP AD KNOWLEDGE PORTAL, AND THESE COME FROM THE ROS MAP COHORT AT RUSH UNIVERSITY MEDICAL CENTER. AND THESE ARE THE THREE PAPERS IN WHICH THESE INDEPENDENT DATA SETS ARE DESCRIBED. SO, OUR THOUGHT WAS TO TRY AND INTEGRATE THE DATA FROM ALL THREE OF THESE DATA SETS IN ORDER TO SEE IF WE CAN IDENTIFY CONSISTENTLY CONSERVED OBSERVATIONS RELATING CELL TYPE CHANGES TO ALZHEIMER'S DISEASE PATHOLOGY AND CLINICAL VARIABLES.SO, AS A SUMMARY, THESE THREE STUDIES ALL PROFILE THE SAME REGION, FRONTAL CORTEX, OF THE HUMAN BRAIN, FROM THE SAME COHORT, THE ROS MAP COHORT AT RUSH UNIVERSITY. BUT THEY HAVE DIFFERENT NUMBERS OF INDIVIDUALS AND REALLY DIFFERENT NUMBERS OF TOTAL NUCLEI PROFILED. SO, ESSENTIALLY AS TIME HAS GONE ON, WE'VE IMPROVED OUR ABILITY TO PROFILE LARGER AND LARGER NUMBERS OF NUCLEI FROM EACH INDIVIDUAL. SO, THE FIRST TASK IS REALLY TO TAKE THESE THREE DISPARATE DATA SETS AND INTEGRATE THEM USING STANDARD COMPUTATIONAL TECHNIQUES. NOW AS YOU CAN SEE IN THIS FIGURE, WE WERE ABLE TO SUCCESSFULLY INTEGRATE THEM SUCH THAT IN THIS LOW-DIMENSIONAL REPRESENTATION THE MAJOR CELL TYPES FROM ALL THREE STUDIES OVERLAP QUITE NICELY.ONCE WE'VE DESCRIBED THESE MAJOR CELL TYPES, WHAT WE NEXT NEED TO DO IS IDENTIFY THE SMALLER SUBTYPES, OR FINER SUBTYPES THAT EXIST IN EACH OF THESE DATA SETS ACROSS ALL OF THEM. AND A JOINT CLUSTERING APPROACH ON THIS ENTIRE DATA SET IDENTIFIES THESE CELL TYPES AND WE CAN SEE HERE IN THIS DOT PLOT THAT THESE MAJOR CLASSES OF CELLS, SUCH AS GLUTAMATERGIC NEURONS, GABAERGIC NEURONS, AND THEN THE VARIOUS GLIAL CLASSES CAN ALL BE FURTHER SUBDIVIDED INTO SMALLER SUBTYPES, EACH OF WHICH HAS A UNIQUE COMBINATION OF MARKER GENES THAT IS SUFFICIENT TO DESCRIBE IT. AND THIS REALLY IS THE POWER OF THE SINGLE NUCLEUS RNA SEQUENCING STUDIES, AS YOU'VE HEARD, IS THAT THEIR ABILITY TO RESOLVE AT THIS FINER LEVEL SOME OF THESE CELL TYPE DIFFERENCES.BUT THE REAL QUESTION HERE IS, WE WANT TO ASSOCIATE CHANGES IN THE PROPORTIONS OF THESE CELL TYPES, OR SUBTYPES, WITH AD CLINICAL AND PATHOLOGICAL FEATURES. AND WHAT WE SEE HERE IS -- ON THE RIGHT IS AN ASSOCIATION ANALYSIS SHOWING THE ASSOCIATION OF VARIOUS CELL SUBTYPES SPECIFICALLY WITH THE QUANTIFIED -- QUANTIFICATION OF THE TAU OR NEUROFIBRILLARY TANGLES IN THESE POST-MORTEM BRAIN SAMPLES. AND WHAT YOU SEE HERE IS THAT THERE ARE CERTAIN CELL TYPES IN WHICH BOTH THE SIGNIFICANCE AS WELL AS THE DIRECTIONALITY OF THEIR CELL TYPE PROPORTIONS ARE REALLY CONSERVED IN ALL THREE OF THE DATA SETS THAT WE HAVE HERE.SO, FOR EXAMPLE TWO OF THESE RORB-POSITIVE EXCITATORY NEURONS SUBTYPES APPEAR TO BE DEPLETED WITH INCREASING TAU PATHOLOGY, WHEREAS THE SOCS3 POSITIVE ASTROCYTE SUBTYPE SEEMS TO BE ENRICHED OR PREFERENTIALLY UP -- FORMING THE GREATER PROPORTION WITH INCREASING TAU PATHOLOGY. AND THIS IS IMPORTANT BECAUSE THESE FINDINGS WERE NOT CONSISTENTLY OBSERVED IN ALL THREE PUBLICATIONS, BUT WHEN WE BRING THE DATA TOGETHER IT HIGHLIGHTS THAT THESE CHANGES SEEM TO BE ROBUSTLY PRESENT IN ALL OF THESE THREE DATA SETS. SO, REALLY WHAT THIS LEADS US TO IS THE USE OF THESE TYPES OF CONSISTENT ASSOCIATIONS THAT COME FROM THESE INTEGRATIVE ANALYSES TO HELP PRIORITIZE TARGET CELL TYPES FOR INTERVENTION AND EXPLORATION. ESSENTIALLY, IF WE'RE SEEING THE SAME ASSOCIATION BY CELL TYPE TO PATHOLOGY OR CLINICAL TRAIT IN MULTIPLE SINGLE NUCLEUS DATA SETS, THAT GIVES US MORE CONFIDENCE THAT THAT IS A CELL TYPE TO WHICH WE SHOULD PAY MORE ATTENTION, OR FURTHER EXPLORE IN THE CONTEXT OF ALZHEIMER'S DISEASE.SO, REALLY WHAT WE'VE DONE HERE IS ESTABLISH A BASIC FRAMEWORK TO TRY AND INTEGRATE THESE DATA SETS, BUT ALSO COME UP WITH A DOWNSTREAM ANALYSIS, FOCUSING SPECIFICALLY ON CONSERVATION OF CELL TYPE CHANGES. AND THE LANDSCAPE HERE, AS YOU'LL HEAR IN THIS -- THROUGHOUT THE SUMMIT, IS REALLY THE NOTION OF FINDING REPRODUCIBLE SIGNATURES ACROSS ALL OF THESE VARIOUS CONSORTIA AND EFFORTS, BOTH WITHIN THE AD KNOWLEDGE PORTAL AS WELL AS EXTERNAL CONSORTIA AND COLLABORATIONS WITH PSYCHENCODE, THE ALLEN INSTITUTE, AND THE BICCN AT NIH. AND REALLY WHAT WE HOPE TO DO IS PRIORITIZE THESE CELL TYPES BY FINDING THE ONES FOR WHICH WE FIND THE MOST CONSISTENT SIGNATURES ACROSS MULTIPLE STUDIES AND CONSORTIA. IN ORDER TO DO THIS, OF COURSE, WE WOULD NEED A UNIVERSAL NOMENCLATURE TO TRANSLATE ACROSS ALL THESE STUDIES AND ED LEIN AT THE ALLEN INSTITUTE IS ACTUALLY GOING TO TALK NEXT IN THE LIGHTNING SERIES ABOUT HOW WE CAN DO THIS TYPE OF TASK.AND FINALLY, WE NEED STANDARDIZED WORKFLOWS FOR CROSS DATASET ANALYSES, REALLY READING -- LEADING TO RIGOR AND REPRODUCIBILITY ACROSS OUR DATA AND ANALYSES. AND YOU'LL HEAR MORE ABOUT THIS FROM ANNA GREENWOOD AT SAGE BIONETWORKS. SO REALLY, WE'RE POISED WITH THE ADVENT OF ALL OF THESE SIMULTANEOUS STUDIES FROM MULTIPLE GROUPS AND CONSORTIA TO TRY AND GET AN OVERALL VIEW OF WHICH CELL TYPES SEEM TO BE CONSISTENTLY ASSOCIATED WITH CHANGES IN ALZHEIMER'S DISEASE AND ARE LIKELY TO BE THE MOST VIABLE TARGETS FOR MANIPULATION AND THERAPY. THANK YOU VERY MUCH. THE TITLE OF MY TALK IS, AN OPEN SCIENCE APPROACH TO BRING THE TOOLS AND KNOWLEDGE OF THE BRAIN INITIATIVE TO ALZHEIMER'S DISEASE RESEARCH.ONE OF THE GREAT CHALLENGES OF STUDYING HUMAN BRAIN FUNCTION AND DISEASE IS THE EXTRAORDINARY COMPLEXITY OF THE HUMAN BRAIN AND ITS INACCESSIBILITY FOR STUDY, WHICH HAS REALLY HAMPERED OUR ABILITY TO HAVE A PRECISE UNDERSTANDING OF HUMAN FUNCTION AND DYSFUNCTION IN THE BRAIN.HOWEVER, MAJOR ADVANCES THROUGH THE NIH BRAIN INITIATIVE AND OTHER LARGE PROJECTS, THAT ARE FUELED BY TRANSFORMATIVE SINGLE-CELL TECHNOLOGIES, ARE REALLY CHANGING THIS SITUATION SIGNIFICANTLY. IN PARTICULAR, THE BRAIN INITIATIVE CELL CENSUS NETWORK, OR BICCN, HAS REALLY RECOGNIZED THE POWER OF THESE SCALABLE SINGLE-CELL TECHNOLOGIES, TO BE ABLE TO CREATE A DETAILED CELL CENSUS OF THE BRAIN.NOW, WE'VE BEEN PART OF THESE EFFORTS TO HAVE A COORDINATED EFFORT TO DEFINE THE CELLULAR AND CIRCUIT ARCHITECTURE OF THE BRAIN, AND CROSS-SPECIES AS WELL, IN MOUSE, IN MONKEY, AND IN HUMAN. THIS EFFORT HAS REALLY BEEN QUITE REMARKABLE IN BRINGING TOGETHER EXPERTISE FROM A NUMBER OF DIFFERENT DOMAINS, TO CHARACTERIZE CELL TYPES AS AN ABSTRACTION OF THE COMPLEXITY OF THE BRAIN, THAT CAN BE QUANTITATIVELY CHARACTERIZED ON THE BASIS OF SINGLE CELL OMICS, RNA-SEQ, ATAC-SEQ METHYLATION. THERE'S SPATIAL DISTRIBUTIONS, THERE ARE PATTERNS OF CONNECTIVITY AND FUNCTION. AND THE OUTPUT OF THIS IS REALLY TURNING INTO A HIGHLY DETAILED QUANTITATIVE CLASSIFICATION OF CELL TYPES, THAT'S FUNDAMENTALLY ROOTED IN MOLECULAR GENETICS, OR MOLECULAR IDENTITY OF CELLS. AND TO JUST GIVE A LITTLE IDEA OF WHAT THIS LOOKS LIKE, ON THE UPPER RIGHT HAND SIDE HERE, IS THE SUM OUTPUT OF THE FIRST MAJOR EFFORT OF THE BICCN TO CHARACTERIZE CELLS IN THE PRIMARY MOTOR CORTEX.AND WHAT YOU CAN SEE IS A HIERARCHICAL ORGANIZATION OF ABOUT 100 KINDS OF CELLS THAT CAN BE DISCRIMINATED ON THE BASIS OF THEIR GENE EXPRESSION PATTERNS, ON THEIR EPIGENETIC REGULATION, AND ON THEIR OTHER CELLULAR PHENOTYPES. SO THIS IS A MUCH MORE GRANULAR UNDERSTANDING OF CELLULAR COMPLEXITY THAN WE'VE EVER HAD BEFORE, AND IT REALLY HAS BEGUN TO BUILD A KNOWLEDGE ARCHITECTURE, A KNOWLEDGE BASE, AROUND THESE CELL TYPES, THAT FORMS A GREAT FOUNDATION FOR STARTING TO UNDERSTAND DISEASE.FURTHERMORE, THIS MOLECULAR GENETIC DEFINITION OF CELL TYPES ALSO LEADS DIRECTLY TO UNDERSTANDING GENE REGULATORY MECHANISMS UNDERLYING THAT IDENTITY, AND THE IDENTIFICATION OF ENHANCERS THAT CAN DRIVE CELL TYPE SPECIFIC EXPRESSION, IN NON-GENETICALLY TRACTABLE ORGANISMS. WHICH ARE GREAT FOR BASIC RESEARCH, AND AS I'LL MENTION, ALSO POTENTIALLY VERY IMPORTANT FOR THERAPEUTICS.SO THIS FOUNDATION HAS REALLY SET THE STAGE FOR GAINING A MUCH BETTER UNDERSTANDING OF ALZHEIMER'S DISEASE PATHOLOGY. AND WE'VE NOW BEGUN A PROJECT, FUNDED BY NIA, IN COLLABORATION WITH THE ALLEN INSTITUTE, THE UNIVERSITY OF WASHINGTON, AND KAISER PERMANENTE WASHINGTON HEALTH RESEARCH INSTITUTE, TO BRING TO BEAR THESE TYPES OF TECHNOLOGIES TO GAIN A MUCH BETTER, HIGHLY GRANULAR UNDERSTANDING OF ALZHEIMER'S PATHOLOGY, THROUGH THIS LENS OF CELL TYPES.AND WE ARE IN THE PROCESS NOW OF APPLYING THESE TOOLS, IN PARTICULAR SINGLE CELL TRANSCRIPTOMICS, EPIGENOMICS AND SPATIAL TRANSCRIPTOMICS, TO UNDERSTAND THE SPECTRUM OF AD PATHOLOGY, ESPECIALLY IN EARLY STAGES.WITH A CAREFULLY CONTROLLED COHORT, WE'RE ABLE TO STUDY THE RELATIONSHIPS BETWEEN AGING AND DISEASE RELATED CLINICAL PHENOTYPES, AND TO BEGIN TO UNDERSTAND RESISTANCE AND RESILIENCE. WITH THE FOUNDATIONAL IDEA, FUNDAMENTAL IDEA, THAT BY STARTING WITH THIS UNDERSTANDING OF THE CELLULAR DIVERSITY IN THE NERVOUS SYSTEM, WE CAN THEN LOOK AT ALZHEIMER'S TISSUES, WE CAN MAP THOSE ALZHEIMER'S TO THE REFERENCE FRAMEWORK FROM THE NORMAL ADULT, AND WE CAN ASK QUESTIONS SUCH AS, ARE SOME CELL TYPES SELECTIVELY VULNERABLE AND RESISTANT, CAN WE DEFINE ALZHEIMER'S AS AN AGING TRAJECTORY THAT'S ABERRANT, AND TO TRY TO BEGIN TO UNDERSTAND WHAT MOLECULAR PATHWAYS ARE PERTURBED, AND WHICH CELL TYPES, AND HOPEFULLY, WHERE'RE THE BEST CELLULAR MOLECULAR TARGETS FOR INTERVENTION.AND I'M GOING TO INTRODUCE AN IDEA HERE, WHICH IS THAT IN ADDITION TO MOLECULAR PATHWAYS, PERHAPS CELL TYPES CAN BE TARGETS FOR INTERVENTION. IF WE CAN FIND VULNERABLE CELL POPULATIONS OR PERTURBED CELL POPULATIONS, WE NOW HAVE THE TOOLS TO BE ABLE TO DEVELOP VERY PRECISE WAYS TO SELECTIVELY, GENETICALLY MANIPULATE THOSE. IN THIS BOTTOM RIGHT HAND PANEL HERE IS SHOWN A FEW AAB DELIVERED VECTORS THAT HAVE CELL TYPE SPECIFICITY BY VIRTUE OF HAVING A SHORT ENHANCER SEQUENCE THAT CAN TARGET A PARTICULAR CELL TYPE. SO IF WE CAN IDENTIFY THOSE CELL TYPES, WE ACTUALLY HAVE THE TOOLS NOW TO BEGIN TO TARGET THEM.SO, WE HAVE THIS VERY POWERFUL SET OF NEW TOOLS, AND THE KNOWLEDGE BASE FROM THE BRAIN INITIATIVE, THAT FORMS THE FOUNDATION FOR HOPEFULLY GAINING A MUCH BETTER UNDERSTANDING OF ALZHEIMER'S, AS OTHERS ARE DOING TOO.I ALSO WANT TO PROMOTE THAT I THINK THESE ARE VERY, VERY BIG PROBLEMS, AND SOME OF THE OTHER LESSONS THAT WE'RE LEARNING FROM THE BASIC SCIENCE ARENA TRANSLATE VERY STRONGLY HERE TO THE ALZHEIMER'S COMMUNITY, AND WE HOPE TO BE A BRIDGE FOR THAT. IN PARTICULAR, OPEN DATA SHARING, AS WE'VE ALWAYS ESPOUSED AT THE ALLEN INSTITUTE, AND THROUGH THE BICCN, AND OTHER VERY LARGE CONSORTIUM EFFORTS, SUCH AS THE HUMAN SOL ATLAS, AND I WANT TO POINT OUT THE AD KNOWLEDGE PORTAL ALSO SUPPORTS THIS MENTALITY, THAT WE NEED TO SHARE DATA OPEN, EARLY, AND IN AS ACCESSIBLE A MEANS AS POSSIBLE.AND IN ORDER TO FACILITATE THAT TYPE OF SHARING, WE REALLY ALSO HAVE TO THINK ABOUT STANDARDS A LOT. SO, I'VE ALREADY MENTIONED THE REFERENCE CELL TYPE CLASSIFICATIONS THAT I THINK CAN BE A STARTING POINT FOR ALL OF THESE TYPES OF STUDIES, AND WE INTEND TO CREATE TOOLS TO ALLOW OTHERS TO MAP THEIR DATA TO THAT, AND TRANSFER LABELS OVER, SO THIS IS A STARTING POINT AKIN TO REFERENCE GENOMES. BUT ALSO, INCREASED FOCUS ON ANATOMY AND STANDARD ANATOMICAL FRAMEWORKS, SO WE CAN MAP THINGS INTO COMMON COORDINATE FRAMEWORKS, AND COMPARE ADEQUATELY ACROSS STUDIES, AS WELL AS EVEN MOVING TOWARDS SOME OF THE MORE TECHNOLOGICAL ELEMENTS OF HUMAN TISSUE BANKING AND DATA QUALITY STANDARDS, AND BASIC CLINICAL PHENOTYPING.SO IN SUMMARY, WE REALLY ARE AT A POINT NOW WHERE THE TOOLS OF THE BRAIN INITIATIVE AND THE INVESTMENTS IN UNDERSTANDING THE FIND ORGANIZATION OF THE HUMAN BRAIN, WHICH ARE QUICKLY MOVING FROM MOUSE BRAIN TO HUMAN BRAIN, AND FROM DISCREET BRAIN REGIONS TO WHOLE BRAIN, ARE REALLY FORMING AN AMAZING FOUNDATION TO GAIN A MUCH BETTER, HIGHLY GRANULAR UNDERSTANDING OF ALZHEIMER'S DISEASE AS WELL, WITH THE PROMISE, I HOPE, OF BEING ABLE TO FIND NEW TARGETS AND NEW THERAPEUTICS IN THE FUTURE. AND WE REALLY HOPE THAT WE CAN HELP TO BE A BRIDGE BETWEEN THESE WORLDS. THANK YOU VERY MUCH FOR THE OPPORTUNITY TO SPEAK HERE TODAY. HELLO, EVERYONE. IÍM GOING TO TELL YOU A LITTLE BIT ABOUT HOW ARTIFICIAL INTELLIGENCE AND MACHINE LEARNING CAN ACCELERATE DIAGNOSIS, DRUG DISCOVERY, AND PRECISION MEDICINE, USING WORLDWIDE DATA. THIS IS JOINT WORK WITH MY COLLEAGUES WHO WORK ON THE AI4AD PROJECT. THIS IS A NEWLY FUNDED NIA INITIATIVE TO APPLY ULTRASCALE MACHINE LEARNING FOR DISCOVERY IN ALZHEIMERÍS DISEASE BIOBANKS.SO, WHILE THE REAL CHALLENGE IS, AND FUTURE GROWTH AREAS FOR ARTIFICIAL INTELLIGENCE IS TO APPLY IT TO PRECISION MEDICINE. IN OTHER WORDS, TO COLLECT ALL OF THE AGGREGATED BIOMARKER DATA FROM AS MANY PATIENTS AS POSSIBLE ACROSS THE WORLD. THIS COULD BE THE GENETIC CODE, IT COULD BE OMICS DATA, IT COULD BE PLASMA MARKERS. AS YOU SEE ON THE LEFT THERE, IT COULD BE NEUROIMAGING, OR EVEN MOBILITY DATA. AND USE ALL OF THIS INFORMATION TO CREATE A MATHEMATICAL MODEL, OR A STATISTICAL MODEL, TO MAKE DECISIONS OR PREDICTIONS ABOUT INDIVIDUAL PATIENTS.IT MIGHT BE THE DIAGNOSIS, THE PROGNOSIS, THE LIKELY RESPONSE TO DIFFERENT TREATMENTS. AND ITÍS BEEN FOUND THAT AI METHODS CAN DISCOVER AND LEARN PATTERNS IN BIOBANKS OF DATA FROM PATIENT POPULATIONS. AND THIS IS VERY IMPORTANT AND USEFUL. SO MACHINE LEARNING METHODS, IF WE CAN TRAIN THEM AND USE THEM FOR DIAGNOSIS, SUBTYPING, PARTICULARLY IN ALZHEIMERÍS DISEASE, AND IN THE ATNV SUB-TYPING FRAMEWORK, WE CAN TRY AND UNDERSTAND WHAT PATHOLOGIES THE PATIENTS HAVE, AND ALSO WHAT TREATMENTS MIGHT BE BEST.SO HEREÍS SOME WORK BY DUYGU TOSUN. SHEÍS A PROFESSOR AT UCSF WORKING ON OUR AI4AD PROJECT. AND SHEÍS USING MACHINE LEARNING TO INFER NEUROPATHOLOGY AND PERFORM DISEASE SUB-TYPING. SO, YOU CAN IMAGINE THE CERTAIN MIXED PATHOLOGIES IN THE BRAIN, EVEN AMONG PEOPLE WITH ALZHEIMERÍS DISEASE, THAT MIGHT NOT BE OBVIOUS UNTIL POST-MORTEM DATA VERIFIES WHETHER THESE PATHOLOGIES ARE THERE.THEY COULD BE TDP-43, THEY COULD BE LEWY BODIES, THEY COULD BE ANGIOPATHY, BLOOD VESSEL CHANGES THAT MIGHT NOT BE EVIDENT. SO SHEÍS BEEN USING NOT JUST DEMOGRAPHIC DATA ON THE AGE, SEX, AND GENOTYPE OF THE INDIVIDUALS, BUT ALSO NEUROIMAGING DATA FROM AMYLOID AND TAU SENSITIVE PET, AND OTHER MODALITIES THAT CAN ALL BE COLLECTED FROM PATIENTS, TO TRY AND PREDICT WHAT PATHOLOGIES PEOPLE HAVE, TRAINING ON DATA WHERE POST-MORTEM DATA IS AVAILABLE TO VERIFY WHETHER THE ALGORITHM IS CORRECT. AND THIS DOES A TERRIFIC JOB. IT CAN IDENTIFY ALL THESE CO-MORBID PATHOLOGIES WITH 86-89% ACCURACY. AND YOU CAN IMAGINE THAT WHEN THIS IS APPLIED TO NEW PATIENTS, WHERE OBVIOUSLY THE AUTOPSY DATA IS NOT AVAILABLE, IT MIGHT IDENTIFY SUB-GROUPS OF PATIENTS, MAYBE IF SOMEONE HAS VASCULAR DISEASE THEY MIGHT RESPOND TO A VASCULAR TREATMENT. IF THEY HAVE AMYLOID OR TAU PATHOLOGY, THEY MIGHT BE ENROLLED IN AN ANTI-AMYLOID OR ANTI-TAU DRUG TRIAL.AND ALSO, SUB-TYPING IS ALSO USEFUL TO IDENTIFY RISK FACTORS IN THE GENOME AND ENVIRONMENT. BY JUST BETTER DEFINING THE BIOLOGY, TO SORT OF STRATIFY PATIENTS INTO MORE HOMOGENOUS SUB-GROUPS.SO, ANOTHER APPLICATION OF ARTIFICIAL INTELLIGENCE THAT IS EXTREMELY EXCITING IS FOR GENE DISCOVERY AND DRUG DISCOVERY. AND SO, AS PART OF AI4AD, OUR NEW INITIATIVE, WEÍRE USING DEEP LEARNING TO DETECT PATTERNS IN WHOLE-GENOME SEQUENCES THAT ARE ASSOCIATED WITH PARTICULAR BRAIN BIO SIGNATURES. SO, YOU CAN IMAGINE THE PROFILE OF ATROPHY IN ALZHEIMERÍS DISEASE, OR THE PROFILE OF AMYLOID OR TAU ACCUMULATION IN THE BRAIN, THERE MIGHT BE CERTAIN MARKERS IN THE GENOME, AND WE KNOW THAT THERE CERTAINLY ARE, THAT PROMOTE THESE PATHOLOGICAL PROCESSES OR PROTECTORS. SO ONE OTHER EFFORTS WITH SARAH AND SASHA ZARANEK AT CURIE CORPORATION AT HARVARD UNIVERSITY IN BOSTON, AND ALSO HENG HUANG, WHOÍS A LEADING RESEARCHER IN ARTIFICIAL INTELLIGENCE, IS BREAKING UP PEOPLEÍS WHOLE GENOME SEQUENCES INTO DIGESTIBLE UNITS THAT CAN BE IMPORTED INTO DEEP-LEARNING ALGORITHMS. AND NOT JUST PARTITIONING THE GENOME, BUT ALSO FINDING THE BEST COMBINATION OF GENETIC MARKERS TO PREDICT WHATÍS HAPPENING IN THEIR BRAINS.SO IF YOU LOOK AT THAT PICTURE OF THE BRAIN ON THE RIGHT THERE, THERE ARE CERTAIN PATTERNS OF PATHOLOGY IN THE BRAIN, PARTICULARLY AS ALZHEIMERÍS DISEASE PROGRESSES, THAT CAN BE ASSOCIATED WITH CERTAIN COMBINATIONS OF BIO-MARKERS, NOT JUST IN THE GENOME, BUT ALSO IN THE PLASMA, AND CSF. AND TO DISCOVER THE METHODS SUCH AS LI SHENÍS DEEP CCA OR CANONICAL COVARIATES ANALYSIS, ACTUALLY GOES INTO GIANT DATABASES AND DISCOVERS THE BEST COMBINATIONS OF BIO-MARKERS TO PREDICT THESE EMERGING PATTERNS OR LATENT PATTERNS IN THE BRAIN IMAGES, AND ESSENTIALLY DISCOVERS THESE BASED ON LEARNING AND VERIFYING THESE PATTERNS IN VAST NUMBERS OF SUBJECTS.MANY OF YOU ARE FAMILIAR WITH POLYGENIC RISK, WHICH ADDS UP YOUR GENETIC RISK ACROSS KNOWN SINGLE NUCLEOTIDE POLYMORPHISMS IN THE GENOME, BUT THIS ALSO CAN CONSIDER STRUCTURAL VARIANCE THAT OTHER FEATURES THAT WE MAY NOT KNOW TODAY. THIS IS ALSO BEING DONE WITH GYNGAH JUN, WHOÍS AN EXPERT IN DRUG DESIGN AND DRUG RE-PURPOSING. AND HER DATABASE IS HELPING US TO SELECT BIO-MARKERS THAT ARE IN DRUGGABLE PATHWAYS AND MIGHT BE HELPFUL FOR DRUG RE-PURPOSING.SO, THANK YOU SO MUCH FOR YOUR ATTENTION. APPRECIATE THE CHANCE TO TALK TODAY. >> WELCOME BACK. WE HAVE EXPERTS IN OUR PANEL HERE FOR SESSION ONE. WE'RE GOING TO GET STARTED WITH THE Q&A. THERE'S BEEN A LOT OF GREAT QUESTIONS ALREADY SUBMITTED SO I WANT TO THANK EVERYONE FOR SENDING IN THOSE QUESTIONS. IT'S NOT TOO LATE IF YOU WANT TO SUBMIT A FEW MORE. I'LL START WITH THE FIRST QUESTION FOR DR. DAVID BENNET. THE QUESTION IS HOW DO GENES AND THE RESILIENCE MODULE COMPARE TO ALZHEIMER'S DISEASE RISK GENES AND ARE THE SAME GENES OR SIMILAR TO GENES THAT ARE FOUNDED IN SUCCESSFUL AGING STUDIES AND WHAT ARE THE BIOLOGICAL PATHWAYS HIGHLIGHTED BY THAT MODULE? >> ALL RIGHT. SO I'LL ANSWER THE FIRST ONE FIRST. THERE'S A LOT OF GO PATHWAYS. IF YOU LOOK AT TABLE FIVE, SARAH'S 2018, I THINK, THE PAPER IN NATURE NEUROSCIENCE ALL THE SIGNIFICANT ONES WHICH IS A LONG LIST AND HARD TO CHARACTERIZE THAT PARTICULAR MODULE AS ANYTHING IN PARTICULAR. IT TURNS OUT THE AD RISK GENES ARE ASSOCIATED WITH VARIOUS BRAIN PATHOLOGIES AS WELL AS RESILIENCE WHICH IS INTERESTING. MODULE 109 ALSO HAS A SMALL DIRECT ASSOCIATION THROUGH THE BETA AND TAU. AND HOW THEY RELATE TO SUCCESSFUL AGING IS A GREAT QUESTION. FROM WHAT I KNOW OF THOSE GENES I THINK THEY'RE DIFFERENT. I THINK A MORE THOROUGH LOOK WOULD BE NEEDED. NEXT FOR ALISON GOATE. WHERE DO AFRICAN AMERICANS SHOW LESS RISK VARIATION WITH THE GENES YOU PRESENTED? >> THANK YOU FOR THE QUESTION. I THINK IT WAS A MISREADING OF THE PICK OUT. IT'S CERTAINLY TRUE FOR APOE AFRICAN AMERICANS WITH AN E4 ALLELE ARE ASSOCIATED WITH A LOWER RISK FOR ALZHEIMER'S DISEASE THAN OTHER POPULATIONS HOWEVER, FOR ADCA7 THE ASSOCIATION BETWEEN ALZHEIMER'S DISEASE AND ADCA7 VARIANT HAS A SLIGHTLY HIGHER RATIO THAN THE VARIANTS IN EUROPEANS. AND FOR SOL ONE IT'S NOT SIGNIFICANT AND HASN'T BEEN LOOKED AT. I'D EXPECT WE'LL SEE SLIGHTLY DIFFERENT VARIANTS AND THE BACKGROUND THERE WILL BE DIFFERENCES IN THE RISK ASSOCIATED WITH THE SAME VARIANTS ACROSS DIFFERENT POPULATIONS. THIS ISN'T A SURPRISING BUT UNDER LIES THE IMPORTANCE OF LOOKING AT DIFFERENT POPULATIONS FINDING DIFFERENT VARIANTS IN THE GENES AND DIFFERENT VARIANTS ACROSS POPULATIONS. THANK YOU. THE NEXT QUESTION IS FOR DR. KELLIS IS THERE A SEX DIFFERENCE IN THE PSYCHOSIS, SCHIZOPHRENIA PHENOTYPE IN ALZHEIMER'S DISEASE CORRESPONDING TO TRANSCRIPT OMS? -- TRANSCRIPTOMES? >> FASCINATING QUESTION. IT'S HUGELY IMPORTANT. IN THE CONTEXT OF ALZHEIMER'S, THE PREVALENE OF AD IS HIGHER IN CERTAIN INDIVIDUALS AND WHAT WE FOUND IN TRANSCRIPTIONAL DATA FEMALES WERE MORE ABUNDANT IN THE HIV ABUNDANCE OF TRANSSCRIPTION SHOWING A GREATER EFFECT ON FEMALE INDIVIDUALS. ON THE AD PLUS POE ON THE PSYCHOSIS SIDE WE'RE FINDING FEMALES HAVE AN INCREASED RISK FOR PSYCHOSIS IN THE RISK OF AD AND IN THE AD PSYCHOSIS DATA COMPARED TO AD WITHOUT PSYCHOSIS WE FOUND AN INCREASED PREVALENCE OF FEMALE CELLS SUGGESTING THAT NOT ONLY IS AD MORE PREVALENT BUT ALSO PSYCHOSIS IN THE CONTEXT OF AD IS MORE PREVALENT AND TRANSCRIPTIONALLY CHANGING. IF YOU LOOK AT THE PATHWAYS ASSOCIATED WITH THE DIFFERENCES THE MALE DIFFERENTIALLY EXPRESSED GENES ARE ASSOCIATED WIN DENDROCYTES AND THERE MAY BE A PROTECTIVE AFFECT FOR DEGENERATION IN MALES BUT NOT FEMALES WHICH PROMPTED US TO LOOK FOR DIFFERENCES IN WHITE MATTER LOSS BETWEEN MEN AND WOMEN AND INDEED FEMALE FEMALES SHOWING MUCH GREATER WHITE MATTER LOSS THAN MALE INDIVIDUALS. AGAIN, DRAMATIC DIFFERENCES BETWEEN SEXES IN EVERY PHENOTYPE WE'VE LOOKED AT. HUGE AREA OF IMPORTANCE. >> THE NEXT QUESTION IS FOR JENNIFER YOKOYAMA. THE EARLIER ONSET OF AD EXAMPLES ARE FOUND WITH BIOMARKERS DUE TO MISDIAGNOSIS SEEMS IN CONTRAST TO WHERE THE PO AD WAS HIGHLY ENRICHED WITH LOAD SIGNAL. WHAT DO YOU SEE AS THE DIFFERENCE IN THE RESULTS? >> GREAT QUESTION. SO WITH REGARDS TO THE BIOMARKERS, THEY WERE INDEED SELECTED TO BE AMYLOID POSITIVE SELECTIVE PLASMA IF PET IMAGING WASN'T AVAILABLE AND THE DIAGNOSES WERE CONFIRMED AND WITH THE DIFFERENCE IN THE FINDINGS COMPARED TO PREVIOUS REPORTS, I THINK ONE CONTRAST MIGHT BE THAT A LOT OF OUR CASES ARE ACTUALLY ATYPICAL PRESENTATIONS OF EARLY ONSET AD. SO WE DID HAVE A SMALLER PROPORTION VERSUS INDIVIDUALS SHOWING POSTERIOR LEUKOPENIC ATROPHY AND WE HAD THE SAME QUESTION OURSELVES WHETHER IT WAS DUE TO MISDIAGNOSIS AND COMPARED WHAT IT LOOKED LIKE IN LOAD VERSUS FTD AND THE WHOLE PATTERN OF ENRICHMENT IS DIFFERENT. WE DON'T THINK IT'S JUST THAT THERE ARE SOME INDIVIDUALS IN OUR COHORT MISDIAGNOSED BUT PERHAPS DUE TO THE NATURE OF THE DIFFERENT PATTERNS OF NEURON ANATOMIC DEFINITION OF TAU MAY BE LENDING ITSELF TO THE HETEROGENEITY IN RISK VERSUS THE COHORT WE HAVE. >> WE HAVE A QUESTION TO THE PANEL IN GENERAL IF YOU'D LIKE TO ANSWER JUST CHIME IN. SINCE DR. BARNE'S PLENARY THIS MORNING I'VE HEARD FEW SPEAKERS SPEAK ABOUT THE REPRESENTATIVENESS OF THEIR SAMPLES OR DISCUSSED HOW THE LACK OF INCLUSION OR SELECTION ISSUES MIGHT AFFECT YOUR RESULTS. CAN ANY OF THE SPEAKERS DISCUSS WHY ADVANCES TO DECONSTRUCT OF THE BIOLOGY OF THE DISEASE UPDATE AND DESCRIBED BY THE SPEAKERS TODAY SEEMS TO OPERATE IN ISOLATION THE SOCIAL FORCES THAT SHAPE HEALTH AND DETERMINE INCLUSION IN OUR RESEARCH. >> I'LL START OUT. KWHOO WE FOUND IS THE WHAT WE FOUND IS INCLUSION IS CRITICAL AS DESCRIBED BY DR. BARNES. WHAT WE HAVE DONE IS ASKED AT THE BASIC SCIENCE AND FUNDAMENTAL SCIENCE LEVEL, DOES THIS APPLY ACROSS DIFFERENT RACES IN PARTICULAR IN WOMEN. AND OUR RESULTS HAVE SHOWN THAT OUR SCIENTIFIC DISCOVERIES AT THE BENCH HAVE LA TRANSLATED TO THE DIVERSE GROUP OF WOMEN, HISPANIC AND BLACK AND WHITE WOMEN. I THINK THE CALL TO ACTION IS CRITICAL AND THERE'S ENCOURAGING EVIDENCE THAT AT THE DISCOVERY LEVEL WHY THE BRAIN IS DEVELOPING ALZHEIMER'S DISEASE THAT IS APPLICABLE ACROSS RACES. >> I'D LIKE TO HELP ELABORATE ON THIS. THIS IS PHILLIP DE JAGER. HISTORICALLY WE WERE LIMITED IN TERMS OF WHAT SAMPLES WERE AVAILABLE TO US FOR SOME OF THESE STUDIES AND A LOT OF THEM STARTED OFF AROUND SINGLE COLLECTIONS. AND WE'RE GROWING FOR MORE DIVERSE POPULATIONS SO THE SECOND GENERATION WAVE HAS BEGUN AND THOUGH NOT CLEAR IN PRESENTATIONS TODAY, WILL BE COMING SOON AND ONE EFFORT BY THE MPE PROGRAM A SECOND CYCLE TO PRODUCE DATA FROM OVER 660 MINORITY INDIVIDUALS, BRAINS FROM PEOPLE WHETHER LATINX OR AFRICAN AMERICAN FROM MULTIPLE REGIONS AND PRODUCE A DEEP RICH DATA SAMPLED ACROSS COHORTS POINTING TO ALL AVAILABLE RESOURCES WE COULD TO BEGIN TO BEGIN TO GENERATE THE DATA. THIS IS JUST THE BEGINNING AND WE NEED MORE DEDICATED EFFORTS TO COLLECT WELL CHARACTERIZED SAMPLES FROM A MUCH MORE DIVERSE GROUP OF INDIVIDUALS. >> IN THE INITIAL ROUND OF THE AD SEQUENCING PROJECT, WE PRIMARILY SEQUENCED EUROPEAN COHORTS BECAUSE THAT IS WHAT WAS AVAILABLE BUT IN THE SECOND ROUND WE FOCUSSED ON GENERATING NEW COHORTS FROM DIVERSE POPULATIONS AND THERE'LL BE A LOT MORE WHOLE GENOME SEQUENCING DATA AVAILABLE WITHIN THE NEXT YEAR FROM DIVERSE COHORTS WHICH SHOULD REALLY HELP IN IDENTIFYING WHERE VARIANTS IN THESE DIFFERENT POPULATIONS. AS I POINTED OUT IN MY STUDY, I THINK IT'S EXTREMELY IMPORTANT THAT WE STUDY ALL HUMAN POPULATIONS NOT FOCUS ON ONE AS WE HAVE DONE TO DATE. >> I'M FROM COLUMBIA. THIS IS THE EFFECT OF THE LIVED EXPERIENCE ON SOME OF THE DATA MODALITIES AND HOW WE MEASURE THAT. I THINK REALLY THAT'S A COMBINATION OF THIS MULTIMODAL TECHNIQUE AND THE AFFECTS ON THINGS LIKE PERIPHERAL BLOOD MEASURES AND QUESTIONNAIRES THAT GET TO A BROADER RANGE OF THE LIVED EXPERIENCE THAN PERHAPS SOME OF THE FIRST GENERATION OF COHORTS. I THINK THESE ARE SOME OF THE THINGS ALSO ONGOING HELPING TO BRING TOGETHER THE VARIOUS ASPECTS OF THE RISK FACTORS AND RESILIENCE FACTORS. >> AND I'LL JUST ADD A PLUG FOR THE EXPOSOME TALK ON THURSDAY WHICH WILL EXPLORE SOME OF THE PSYCHOSOCIAL VARIABLES TALKED ABOUT IN RELATION TO THE BRAIN OMICS. AT THIS POINT, IT'S IN NON-LATINO WHITES WITH MORE SEQUENCING OVER TIME WE'LL BE ABLE TO SEE TO WHAT EXTENT IS REPLICABLE. >> FROM A FUNCTIONAL POINT OF VIEW, I THINK A FIELD MOVED TO REALIZING IPAC. THESE CELLS ARE PATIENT DERIVED CELLS AND FROM THE DISCOVERY WE HAVE TOOLS NOW TO ADDRESS THE DIVERSE QUESTION. >> I'M CURIOUS ABOUT THE RESILIENCE CHANGES IN YOUR MOUSE POPULATIONS AND ONE IS A GENE OF INTEREST. >> GREAT QUESTION. SORRY, I DIDN'T HAVE TIME TO FIT IT ALL IN. THE GENES WERE DERIVED FROM GENE ANALYSIS IN SINGULAR NUCLEAR DATA GENERATED FROM AD MICE EITHER DIAGNOSED AS RESILIENCE OR SUSCEPTIBLE AND WHETHER OR NOT THE DIFFERENTLY EXPRESSED GENES WERE REPLICATED DIFFERENTLY EXPRESSED IN THE SAME DIRECTION IN HIPPOCAMPAL AND PROTEOMICS DATA FROM MOUSE STRAINS AND HUMAN BRAINS BEING DIFFERENTIALLY EXPRESSED. THERE ARE TIER ONE HITS CHANGING IN THE SAME DIRECTION AND REPLICATED ACROSS MULTIPLE DATA SETS. THE NEXT QUESTION IS TO ED. THE QUESTION IS HOW BIG OF A REFERENCE DO WE NEED TO HAVE IN TERMS OF THE NEUROTYPICAL REFERENCE. ARE SUCH INDIVIDUALS AVAILABLE TODAY IN WHAT QUANTITIES? >> THAT'S A TERRIFIC QUESTION. I WOULD SAY SO FAR WHAT WE'VE BEEN IMPRESSED WITH IS THE STEREOTYPE OF WHAT WE SEE IN THE CELLULAR MAKE UP OF THE BRAIN ACROSS INDIVIDUALS AND IT'S QUITE WELL CONSERVED ACROSS SPECIES AS WELL. SO IT SEEMS A SMALL NUMBER SAY IN THE ORDER OF 6 TO 12 INDIVIDUALS IS ACTUALLY SUFFICIENT SPREAD ACROSS MALES AND FEMALES TO GENERATE SOMETHING THAT CAPTURES THE OVERALL DIVERSITY. ON THE OTHER HAND, MUCH LIKE THE GENOME, YOU CAN BUILD A REFERENCE AND THERE'S A HUGE AMOUNT OF VARIATION RELATED TO MANY ACROSS THE POPULATION. THAT CAN BE BUILT ON TOP OF THAT. I THINK THAT'S WHAT WE'LL SEE HERE AS WELL. THAT REQUIRES MUCH LARGER NUMBERS OF INDIVIDUALS. THE REFERENCES SO FAR AT LEAST HAVE BEEN TRYING TO GET A DEEP UNDERSTANDING OF THE CELLULAR MAKE UP AT A FINAL GRANULARITY ACROSS THE ENTIRE BRAIN. MOST THE FIELD FOCUSES ON A FEW BRAIN REGIONS BUT CHARACTERIZED IN THE HUMAN BRAIN IS A BIGGER TASK. THAT ACTUALLY REQUIRES BRAIN SPECIMENS WELL PREPARED TO BE ABLE TO IDENTIFY REGIONS ACROSS THE ENTIRE BRAIN. THE SECOND HALF OF THE QUESTION ABOUT OUR SUFFICIENT SPECIMENS AVAILABLE, THE ANSWER IS BASICALLY NO AND THINK THERE'S A NEED TO HAVE CAREFULLY PREPARED CONTROLLED SPECIMENS TO DRIVE THESE REFERENCES. AND WE ACTUALLY PUT A LOT OF EFFORT INTO DEVELOPING METHODS FOR OPTIMAL PREPARATION OF BRAIN TISSUES. MY COLLEGIATE THE UNIVERSITY OF WASHINGTON HAS PUT THESE INTO PRACTICE WITH HIS OPERATION. IN AN IDEAL WORLD WHERE ALL BRAINS ARE PREPARED THAT WAY TO BE USED FOR ANY OF THESE TYPES OF STUDIES, I THINK THAT'S GOING GOING TO REQUIRE STANDARDIZATION AND THERE'S EFFORTS TO TRY TO COORDINATE ACROSS VARIOUS BRAIN BANKS TO STANDARDIZE IN A CENTRAL WAY BUT CONTROL SPECIMENS ARE OFTEN MORE DIFFICULT TO GET AND THERE'S NOT ENOUGH AND MORE EFFORTS NEEDS TO GO IN THAT TERRITORY. >> THE NEXT QUESTION IS FOR TONY. IS THERE A WAY TO USE YOUR DATA TO DISCERN WHETHER OR NOT OR NOT ONE OR MORE ORGANS KICKS OFF THE DRIVE FOR THE ASYNCHRONOUS ORGANIZATION OF AGING. >> WE'D LOVE TO FIND OUT WHAT ARE THE EARLIEST CHANGES. AT THIS POINT WE'RE RESTRICTED TO MICE AND WOULD LIKE TO EXPAND TO HUME BRAINS AND THERE'S LIKELY DIFFERENCES BETWEEN MALES AND FEMALES. WE ALREADY START TO SEE THIS IN MICE. THAT TOO IS AN ADDITION QUESTION WE WANT TO PURSUE. >> THE NEXT QUESTION IS FOR DR. LEVINE. THE QUESTION IS CAN EPIGENETIC AGE BE MEASURED REASONABLY WELL IN PERIPHERAL BLOOD WITH EPIGENOME WIDE SCREEN AND FOUND LINK WITH MRI AND BRAIN MEASURES. DO YOU THINK WE'LL SEE THE SAME APOE EFFECT YOU SAW? >> MOST OF THE EPIGENETIC AGING STUDIES HAVE BEEN DONE IN PERIPHERAL BLOOD AND WHAT I SPOKE ABOUT TODAY IS THE MORE SPECIFIC BRAIN. THE ISSUE GOES BACK TO WHAT I WAS TALKING ABOUT THE ASYNCHRONOUS NATURE OF AGING. IF YOU MEASURE THE EPIGENETIC AGING BLOOD IT DOESN'T NECESSARILY REFLECT WHAT THE AGING PATTERN IS IN BRAIN. MY LAB IS INTERESTED IN CAN WE DETECT CHANGES IN BLOOD THAT DO IN FACT REPRESENT BRAIN ALONG WITH THIS DIFFERENTIAL RISK WHETHER IT'S APOE FOUR STATUS OR SEX DIFFERENCES AS MANY PEOPLE ARE INTERESTED. SHORT ANSWER IS YOU CAN MEASURE IT IN BLOOD BUT NOT A PROXY FOR WHAT YOU'D SEE IN THE BRAIN. >> THE NEXT QUESTION IS FOR MATHIAS. WHAT IS THE METABOLIC PROFILE ASSOCIATED WITH RESILIENCE? >> WE LOOKED AT LEVELS IN THE BLOOD AND THE METABOLITES ARE QUITE SENSITIVE MARKERS FOR FOFOR FOFOR DI FOR DISREGULATION OF ENERGY. SOME ARE ACCUMULATING IN -- DYSREGULATION IN ACCUMULATING DISEASE LIKE DIABETES AND SOME OVERLAP WITH AGING IN GENERAL SO WHERN WE LOOK AT THE PEOPLE IN THE CLASS THAT LOOK TO BE RESILIENCE TO AD PROCESSES, THEY LOOK METABOLICALLY MORE HEALTHY IN GENERAL WHEN COMPARED TO METABOLIC SYNDROME AND ALSO LOOK YOUNGER. WE CAN ALL LOOK AT THIS IN RELATION TO OTHER PEOPLE. IN THAT REGARD THEY ACTUALLY JUST LOOK YOUNGER METABOLICALLY MORE FIT. >> THE NEXT QUESTION IS FOR DR. BRINTON. ASKING TO DISCUSS THE AFFECTS OF BRAIN ENERGY STARVATION ON THE BLOOD BARRIER, IMMUNE SYSTEM AND CSF COMPOSITION. ARE THERE EFFECTS KNOWN TO HAPPEN BEYOND THE KEYTONE ADAPTATION? >> IT'S A GREAT QUESTION. COMPLEX WITH RESPECT TO THE FIRST ON THE BLOOD BRAIN BARRIER, WE WERE QUITE SURPRISED, FRANKLY, IT WAS SHOCKING, THAT WE COULD DETECT THAT THE T CELL INFILTRATION WAS OCCURRING VERY EARLY IN MIDLIFE AGING AND THAT IT APPEARS TO BE IN RESPONSE CLEARLY THE BLOOD BRAIN BARRIER HAS OPENED. WE FIND THAT THERE'S AN OPENING AND CLOSING AND OPENING AGAIN DEPENDING UPON THE SEVERITY OF THE IMMUNE RESPONSE. WHAT ESSENTIALLY WHAT WE FIND IS THAT AS THIS TRANSITION IS OCCURRING, THERE'S A LOT OF CROSS TALK BETWEEN THE BRAIN AND THE PERIPHERY, BOTH IN UTILIZATION OF FUELS AND THE IMMUNE RESPONSE AND INFILTRATION INTO BRAIN. SO THE BLOOD BRAIN BARRIER IS OPENING. IS IT BECOMING LEAKY? THERE'S A FAIR AMOUNT OF EVIDENCE TO SUGGEST AND APOE FOUR CARRIERS THE BLOOD BRAIN BARRIER CAN BE MORE LEAKY. IN THE IMMUNE SYSTEM WE FOUND THIS CROSS-TALK BETWEEN THE METABOLIC AND IMMUNE SYSTEM THAT ULTIMATELY LEADS TO METABOLIC REPROGRAMMING TO USE AUXILIARY FUELS AND WHAT OUR WORK HAS SHOWN AND INTERESTINGLY MATHIAS AND MANOLIS, THAT IN THE FEMALE BRAIN THE LOSS OF WHITE MATTER MAY BE BECAUSE THE WHITE MATTER IS A SOURCE OF LIPIDS TO GENERATE THOSE KEYTONE BODIES. SO WHAT WE WOULD ANTICIPATE FINDING IN THE CSF IS WHAT WE FOUND IN THE PLASMA, METABOLITES DERIVE FROM THE LIPID METABOLISM. IT'S DIFFERENT IN THE MALE AS MATHIAS HAS TALKED ABOUT EARLIER AND PUBLISHED IN OUR JOINT PAPER, WE FIND THAT THE BRANCHED AMINO ACIDS AND MATHIAS JUMP IN WHENEVER YOU WANT, THE BRANCHED AMINO ACIDS ARE ELEVATED IN THE MALE AND THAT'S LIKELY BECAUSE THE MALES HAVE A DEPOT OF PROTEINS THAT CAN BE CONVERTED INTO AMINO ACIDS AND BE CONVERTED TO GLUCOSE AND KEYTONE BODIES. THE UNDERLYING HYPOTHESIS IS THAT THIS IS A RESPONSE TO STARVATION IN THE BRAIN. THESE ARE BUILT IN PROGRAMS FOR THE BRAIN TO SURVIVE A STARVATION RESPONSE IN THE SHORT TERM AND THE PROBLEM IS PERHAPS IN ALZHEIMER'S IT'S A LONG-TERM PROBLEM. IT CAN LEAD TO ADVERSE OUTCOMES IN ALZHEIMER'S. >> NEXT QUESTION IS FOR PHIL. ARE YOU ABLE TO IDENTIFY WHERE IPSC MODEL IN TERMS OF STAGES? >> I THINK THE PSEUDOTIME MODELS ARE STILL EVOLVING. AT THIS POINT THEY'RE RELATIVELY -- THEY'RE NOT COMPLETELY STABLE. WE STILL NEED TO DO FURTHER DEVELOPMENT TO BETTER UNDERSTAND HOW TO USE THE TECHNIQUES. AND TO INCORPORATE OTHER DATA. THE LITERATURE SUGGESTS IT SHOULD BE ABLE TO BE DONE TO BETTER ALIGN THE INDIVIDUAL CELL LINES WITH THE TRAJECTORY. WHAT'S NOT CLEAR IS THERE'S NOT A SINGLE TRAJECTORY FROM A TO Z BUT A STARTING POINT NOT WELL DEFINED AND A HOST OF -- PROBABLY A NUMBER OF OUTCOMES AND END POINTS. IT'S GOING TO RESEMBLE MORE OF A TREE THAN A SINGLE LINE. >> THE NEXT QUESTION IS A GENERAL QUESTION FOR THE PANEL. SO REGARDING DISEASE HETEROGENEITY, HOW DO WE DISTINGUISH POTENTIALLY DISTINCT TRAJECTORIES OF DISEASE ASSOCIATED DECLINE THROUGH DIFFERENT STAGES ALONG THE SAME TRAJECTORY AND HOW IS THIS INFLUENCED BY SEX? >> MANY OF US TALKED ABOUT OMICS DATA TO DO SUBTYPING. AS YOU KNOW AND AS THE QUESTIONER ASKED, IF YOU LOOK AT MULTIPLE STAGES OF PROGRESSIVE DISEASE OR STAGES INTERMIXED YOU DON'T WANT THE STAGES TO COME OUT AS SUB TYPES. THERE'S INTERESTING WORK FROM THE UNIVERSITY OF LONDON BY ALEXANDRIA YOUNG WITH A SYSTEM CALLED SUSTAIN AND IMAGINE THERE'S ALL KIND OF PROCESSES ABETA TAU TRAJECTORY IN THE BRAIN AND WHITE METANOMIC INTENSITIES AND CATB43, WHAT SHE HAS STRFLD WITH COLLEAGUES IS -- HAS DEVELOPED WITH COLLEAGUES IS A MODEL OF MARKERS AND AT THE SAME TIME DISENTANGLE THE SUB TYPES SO AT THE SAME TIME YOU AGGREGATE COMMON PATHOLOGIC SPREAD AND SEPARATE DISTINCT SUB TYPES WE LOOKED AT THAT WITH BIO BANK DATA BECAUSE THERE'S SUB TYPING AND CHANGES IN THE PROGRESSIVE DISEASE. THAT'S ONE POSSIBILITY. MAYBE OTHERS CAN LOOK AT THE SEX DIFFERENCE ASPECTS. >> I SHOWED A SLIDE ON THE ANALYSIS ON THE PROGRESSION OF AD ACROSS BRAIN REGIONS ACROSS INDIVIDUALS AND ACROSS CELL TYPES AND WHAT WE FIND IS THAT YOU CAN START PREDICTING PATHOLOGY AROUND WHEN YOU BUILD THOSE ACROSS DIFFERENT INDIVIDUALS AND ACROSS DIFFERENT BRAIN REGIONS YOU'RE FINDING IN SOME CASES THE SAME INDIVIDUALS SHOW DIFFERENT RATES OF AGING OR AD IN DIFFERENT REGIONS AND BETWEEN DIFFERENT CELL TYPES OF THE SAME REGION. I THINK WE'LL LEARN IN THE SAME WAY AD MANIFESTS EXTREME HETEROGENEOUS WAYS BETWEEN INDIVIDUALS AND SEXES, THE TEMPORAL PROGRESSION OF ALZHEIMER'S IS ALSO EXTREMELY HETEROGENEOUS NOT JUST AT THE END POINT OF HOW EFFECTED ARE DIFFERENT INDIVIDUALS IN TERMS OF A BETA, TAU, NEURAL INFLAMMATION ETCETERA AND OTHER SIGNATURES OF AD AND THE TEMPORAL ASPECT IN THE BRAIN REGION SPECIFIC ASPECT AND CELL TYPE SPECIFIC ASPECT WILL ADD A LOT OF TO THAT MANIFESTATION AND THE TIMING OF MANIFESTATION. >> WE STILL DON'T HAVE A GOOD LINKAGE OF THE STATE OF INDIVIDUAL TO THE POST MORTEM. WE COLLECT BRAIN LATER IN LIFE TYPICALLY THAN THE SAMPLES COLLECTED DURING LIFE. THAT'S GOING TO BE THE BIGGEST CHALLENGE TO RESOLVE AND WE'LL HAVE TO INCREASE THE TYPES OF INFORMATION AND INDIVIDUALS BEHAVIOR DIFFERENTLY AND WE SAW THIS WITH THE EFFECT OF E4 BEING DIFFERENT IN INDIVIDUALS WITH DIFFERENT ANCESTRY AND WE SEE DIFFERENT MOLECULAR STATES OF THE BRAIN IN WHICH E4 HAS A SMALLER EFFECT IN PEOPLE WHO ARE THE SAME ANCESTRY. SO AGAIN, LOTS OF DIFFERENT CONFOUNDING VARIABLES THAT WE HAVE TO RESOLVE OVER TIME AND UNTIL WE HAVE A GOOD REFLECTION IT WILL BE DIFFICULT TO DO. >> I WANTED TO ADD THAT BESIDES LOOKING AT SUBSETS OF INDIVIDUALS HETEROGENEOUS THE ACTUAL TRAJECTORY OF COGNITIVE AGING IS A LITTLE PECULIAR. THE RATE INCREASES SEVERAL FOLD AND THAT'S TRUE REGARDLESS OF WHAT BRAIN PATHOLOGIES YOU HAVE AND LITTLE OF WHAT'S CALLED TERMINAL DECLINE IS ACTUALLY ACCOUNTED FOR BY THE BRAIN PATHOLOGIES. MOST THE BRAIN PATHOLOGIES ARE STRONGLY ASSOCIATE WITH THE PRE TERMINAL COMPONENT. SO THERE'S SOMETHING GOING ON IN THE LAST FEW YEARS OF LIFE WHEN YOU'RE STUDYING ONLY DEAD PEOPLE IT'S EASY TO MEASURE BUT WHEN YOU STUDY LIVE PEOPLE, IT'S HARD TO KNOW WHETHER YOU'RE IN THE BEGINNING OF THAT TERMINAL PORTION. THE OTHER THING TO CONSIDER IS TIME TO DEATH WE'RE BASICALLY SAYING THAT THIS PERSON'S IN TERMINAL DECLINE. AND THERE'S BEEN A LONG SLOW DECLINE BEFORE THAT ASSOCIATE WITH THE BRAIN PATHOLOGIES. IT'S COMPLEX. IT'S WHY WE'RE HAVING THIS WHOLE SESSION. >> MAYBE RELATED TO WHAT WAS SAID THAT FILL AMOUNT LEVELS IN PLASMA IN MICE AND HUMANS PREDICT MORTALITY IN THE FINAL YEARS OF LIFE. YOU WONDER WHY THAT IS THE CASE BECAUSE NEURO DEVELOPMENT IS A STRONG PART. >> A QUESTION FOR DENA. DO WOMEN LIVE LONGER OR MEN JUST DIE FIRST? AND DO WE SEE WOMEN LIVING LONGER ACROSS ALL KINDS OF DISEASES? IT'S A COMBINATION OF LOOKING AT RESILIENCE IN WOMEN OR DISEASE IN MEN. >> YOU CAN CALL IT FEMALE LONGEVITY OR MALE MORTALITY ARE THE SAME IN THESE DISEASES AND UNITED NATIONS TELLS US FROM DATA THROUGH THE WORLD HEALTH ORGANIZATION IN EVERY SOCIETY THAT RECORDS MORTALITY ACROSS THE WORLD FROM SIERRA LEONE TO JAPAN, SWITZERLAND AND THE U.S., FEMALES LIVE LONGER AND THIS IS TRUE DURING EPIDEMICS AS IS THE CASE WITH COVID FEMALES LIVE LONGER WITH SEVERE COVID COMPARED TO MALES AND IT IS TRUE IN EPIDEMICS IN FAMINE WHEN GIRLS LIVE LONGER THAN BOYS IN THE SAME CONDITIONS. I'LL CALL IT FEMALE LONGEVITY ALSO CALLED MALE VULNERABILITY. IT'S ROBUST IN HUMAN POPULATIONS AND WE SEE IT IN ALZHEIMER'S DISEASE. MORE THAN JUST BEING AN INTERESTING DIFFERENCE, WE'D LIKE TO UNDERSTAND WHAT IS IT THAT CONTRIBUTES TO THAT LONGEVITY? WE DON'T WANT TO LIVE LONGER AND MORE MISERABLY, BUT IS THERE A BIOLOGIC MECHANISM FROM LONGEVITY WE CAN APPLY TO UNDERSTAND RESILIENCE AND THAT'S WHERE OUR WORK ON UNDERSTANDING DIFFERENCES BETWEEN XX AND XY COMES IN. I'LL BRIEFLY OUTLINE A VERY INTERESTING EXPERIENCE THAT ALLOWS YOU TO UNDERSTAND THE MECHANISMS AND THAT IS WE CAN GROW MICE THAT ARE XX THAT GROW UP FEMALE WITH OVARIES OR MALE AS TESTIES AND THEN XY MICE WITH OVARIES OR WITH TEST ES AND IT'S THE XX MICE IN NORMAL AGING OR MODELLING ALZHEIMER'S DISEASE, THE XX MICE LIVE LONGER. IT'S QUITE REMARKABLE. THERE'S SOMETHING ABOUT THE SECOND X CHROMOSOME OR SOMETHING DELETERIOUS IN THE Y CHROMOSOME BUT WE HONE IN AS SOME SOURCE OF RESILIENCE THAT COULD BE APPLIED TO NORMAL AGING AND ALZHEIMER'S DISEASE. >> THAT'S GREAT. THANK YOU. THE NEXT QUESTION IS FOR ALISON BUILDING OFF THE QUESTION WE ASKED ED PREVIOUSLY IN TERMS OF WHAT'S THE SAMPLE SIZE. IN THE CONTEXT OF EXPANDING OMICS IN HUMAN DERIVED MICROGLIA MICROGLIA, WHAT'S THE GAP? AS THE STILL NEEDED THERE? >> MAYBE I CAN GO FIRST. ONE OF THE MOST ROBUST FIND FROM GWAS AND ALZHEIMER'S IS MOST LOCI DON'T INCLUDE THE REGIONS AND THE MOST AFFECTED CELL TYPES ARE HUMAN MICROGLIA AND TRYING TO EXPAND THE METABOLOMICS IN THE MICROGLIA. IT WILL BE IMPORTANT TO KEEP THIS IN MIND. AS WE TRY TO UNDER THE GENETICS OF THE DISPOSITION IT WILL BE IMPORTANT TO DERIVE MICROGLIA MARKERS TO USE THE MARKERS AND PERFORM MAPPING TO FIND NOT ONLY THE CAUSAL VARIANTS BUT BE ABLE TO SPECIFICALLY ANNOTATE THE SPECIFIC MOLECULAR MARKERS. THE SECOND THING IS GOING BACK TO SOMETHING WE DISCUSSED EARLIER AS WE'RE DOING THAT, IT'S GOING TO BE SUPER IMPORTANT TO DO THAT IN A DIVERSE POPULATION. WE KNOW FOR GENETICS STATUS AND GWAS AND MOLECULAR MARKERS INCLUDING WHAT WE DID FOR PDL THE ABILITY TO DO FINE MAPPING AND PRECISE LOCALIZATION WILL INCREASE AS WE INCLUDE MORE DIVERSE POPULATION AND FINALLY ONE OTHER IMPORTANT THING TO KEEP IN MIND IS AS THE RISK VARIATION AFFECTS ELEMENTS IT WILL BE IMPORTANT WE NOT ONLY STUDY THE GENE EXPRESSION BUT AT THE SAME TIME WE START BUILDING RESOURCES STUDYING EPIGENOME AND TRYING TO UNDERSTAND HOW THE THREE DIMENSIONAL STRUCTURE OF THE GENOME IS AT RISK FOR THIS KIND OF DISPOSITION. >> JUST TO ADD TO WHAT HE IS SAYING, TO DO THE STUDIES WE ACTUALLY NEED RELATIVELY FEW NUMBER OF INDIVIDUALS FROM EACH POPULATION TO BE ABLE TO GET USEFUL INFORMATION. THE ORDER OF TENS OF INDIVIDUALS. TO DO THE QUANTITATIVE TRAIT LOCUS MAPPING AND THE METHYLATION QTLs, ETCETERA, WE NEED HUNDREDS OF SAMPLES FOR ACCURACY THAT IS WHERE WE'RE MISSING SAMPLES AT THE MOMENT. THEN AS I PRESENTED IN THE GENETIC STUDIES WE NEED AN ORDER OF MAGNITUDE MORE SAMPLES FOR THOSE GENETIC STUDIES WHERE IDEALLY ONE WOULD LIKE TO SEE SAMPLES OF TENS OF THOUSANDS OF INDIVIDUALS. IT DEPENDS ON THE KIND OF DATA YOU WANT TO COLLECT. THAT WILL REFLECT IN THE NUMBER OF SUBJECTS YOU NEED TO DO THOSE STUDIES. >> ANOTHER QUESTION FOR MORGAN. DOES EPIGENETIC AGE CORRELATE TO CHROMOSOMAL AGE AS DETERMINED BY TELOMERE LENGTHS. I WAS UNDER THE IMPRESSION THAT IS THE BEST WAY TO ASSESS AGING BUT IT SOUNDS LIKE METHYLATION MIGHT BE BETTER. CAN YOU CONTRAST THE TWO? >> YES. SO THERE'S DIFFERENT LEVELS AND IN FACT THERE'S AN EPIGENETIC CLOCK SPECIFICALLY MEANT TO PROXY TELEMERE LENGTH AND THE METHYLATION VERSION SEEMS TO BE A BETTER PREDICTOR OF TRACKING WITH AGE AND DIFFERENT AGING OUTCOMES THAN TELEMERE LENGTH MEASURED ITSELF. I FIND THE EPIGENETIC MEASURES ARE BETTER THAN TELEMERE LENGTH. THEY'RE MORE HIGHLY CORRELATED WITH AGE AND THE DISORDERANCE BETWEEN EPIGENETIC AGE AND IS MORE THAN THE TELEMERE LENGTH BASED ON THE ASSOCIATE WITH AGING OUTCOMES. >> THE NEXT QUESTION IS FOR JENNIFER YOKOYAMA. ARE THERE WAYS TO LOOK AT RISK SCORES IN THEIR NON-EUROPEAN PEOPLE AND IF SO WHERE? >> GREAT QUESTION. IT HIGHLIGHTS SOME POINTS THAT CAME UP EARLIER THE IMPORTANCE OF NEEDING TO ESTIMATE RISK FROM THE RIGHT POPULATION IN ORDER TO BEST ESTIMATE IT IN A RELATED BUT DISTINCT POPULATION. I CAN TELL YOU ABOUT TWO INITIATIVES THAT I'M FAMILIAR WITH AND I ANTICIPATE OTHERS ARE OCCURRING. BOTH THE ONES I KNOW OF ARE IN LATINX POPULATIONS. THE FIRST IS BY A GROUP AT UC SAN DIEGO. SHE'S WORKING ON A STUDY. THEY'LL LOOK AT POLY GENIC RISK SCORES AND RISK ASSESSMENTS IN THEIR MEXICAN POPULATION. THE SECOND SAY STUDY WITH OTHERS ASHDZ OTHER COLLEAGUES ACROSS THE U.S. AND LATIN AMERICA WHERE WE'LL BE COLLECTING PATIENTS IN CONTROLS FROM MULTIPLE COUNTRIES IN SOUTH AMERICA AS WELL AS IN THE U.S. TO LOOK AT ALZHEIMER'S DISEASE AND DEMENTIA. PART OF THAT PROJECT WILL BE TO BASICALLY SET THE STAGE FOR BEGINNING TO DEVELOP BETTER WORK IN ADVERSE POPULATIONS. THERE'S INTEREST FROM INTERNATIONAL COLLEAGUES TO ALSO EXPLORE THESE DIVERSE POPULATIONS TO REALLY GET BETTER AT MAPPING THE GENETIC LOCI FOR THEIR SPECIFIC POPULATION BACKGROUND. >> FOR TONY. WHEN ANALYZING THE PLASMA PROTEOMICS DO YOU TAKE INTO ACCOUNT, MEDICINES, LIFESTYLE, ETCETERA? >> GREAT QUESTION. IT DEPENDS ON THE DATA SETS WE HAVE AVAILABLE. SOMETIMES THESE ARE AVAILABLE AND OFTEN THEY'RE NOT, UNFORTUNATELY. I THINK IF WE LOOK AT LARGE ENOUGH SAMPLES AND WE'VE BEEN FORTUNATE ENOUGH TO HAVE THOUSANDS OF INDIVIDUALS, THEN SOME OF THESE ADDITIONAL COVARIATES ARE LESS IMPORTANT AND WE CAN TRY TO FIND THE GLOBAL PATTERNS OF CHANGES THAT ARE MOST IMPORTANT. AGAIN, IDEALLY YOU HAVE ALL THE PATIENTS AVAILABLE. >> THE NEXT QUESTION IS AGAIN FOR DR. DUVAL. THE QUESTION IS WHAT ARE THE CONTRIBUTIONS OF SEX HORMONES CIRCULATED AND SYNTHESIZED IN THE BRAIN ON SEX-RELATED DIFFERENCES IN AGING AND ALZHEIMER'S DISEASE? >> THAT'S NOT A QUESTION OUR STUDIES ARE DIRECTED AT BUT IT IS TRUE THAT IN FEMALES, ESTROGENS AND PROGESTERONES HAVE IMMEDIATE AND ORGANIZATIONAL LONG-TERM EFFECTS WITHIN THE BRAIN AND THE BODY AND AS DR. BRINTON WOULD TELL YOU PERI MENOPAUSE AND MENOPAUSE HAVE DRAMATIC DECREASES IN THESE HORMONES AND LEAD TO CERTAIN VULNERABILITIES IN THE FEMALE BRAIN. LESS IS KNOWN ABOUT THE LOSS OF ANDROGENS AND FREE TESTOSTERONE IN THE MALE BRAIN BUT STUDIES OUT THERE SUGGEST ALSO THIS IS A DELETERIOUS CHANGE IN THE MALE BRAIN. THERE'S CLEAR AFFECTS OF HORMONES SEX SPECIFIC FOR MALES AND FEMALES DURING REPRODUCTIVE AGING AND OUR STUDIES SHOW HORMONES, YES, ARE DRAMATIC CONTRIBUTING FACTORS BUT THAT SEX CHROMOSOMES ALSO CONTRIBUTE IN BOTH THE MALE AND FEMALE BRAINS. BOTH ARE CONTRIBUTING FACTORS TO TWO SEX DIFFERENCES. >> LET ME JUMP IN AND ADD TO WHAT DENA HAS SAID. A BIG DIFFERENCE IN SEX DIFFERENCES IS WOMEN UNDERGOING MIDLIFE AGING TRANSITION THAT RESULTS IN A DECLINE IN ESTROGEN THROUGHOUT THE BODY INCLUDING THE BRAIN. AND THAT THAT MID LIFE TRANSITION STATE TURNED OUT TO BE AN IMPORTANT STRATEGY FOR UNDERSTANDING THIS TRAJECTORY OF RISK FOR LATE ONSET ALZHEIMER'S DISEASE AND IT TAUGHT US THE RIGHT QUESTIONS TO ASK NOT YESLY THE SAME ANSWERS BUT THE RIGHT QUESTIONS TO ASK OF MALE BRAIN AND AGAIN WE HAVE INTERESTING DATA THAT WE'LL BE SUBMITTING SOON THAT DOES INDICATE THAT THE MALE GONADO HORMONES ARE IMPORTANT TO THE MALE BRAIN AS THE FEMALE HORMONES ARE NOT FEMALE BRAIN AND THE INTERVENING WITH OVARIAN HORMONE THERAPIES, IF YOU WILL, IS TIME DEPENDENT AND THAT INTERVENING WHEN WOMEN HAVE SYMPTOMS PROMOTES RESILIENCE OF THE BRAIN AND REDUCED RISK OF DEVELOPING ALZHEIMER'S DISEASE. AND TREATING LONG AFTER MENOPAUSE IS NOT EFFECTIVE. AGAIN, THIS PRECISION APPROACH TO PREVENTION IS AS IMPORTANT AS PRECISION MEDICINE FOR TREATMENT. >> FOR MANOLIS. WHAT DO YOU SEE AS THE COMPLEX INTERACTION BETWEEN MOLECULAR MECHANISMS FOR COGNITIVE AND PSYCHIATRIC TRAITS AND HOW DO THEY RELATE TO REGIONS OF INTEREST OF GENE EXPRESSION AND FUNCTION? >> THIS IS WHERE THE FIELD IS HEADING IN MANY WAYS. IT'S RELATING THE MOLECULAR TO THE PATHOLOGICAL IS IMPORTANT. WHEN WE TRY TO PREDICT THESE FEATURES AND THE COGNITIVE PHENOTYPES AND ABETA PHENOTYPE AND NEURO INFLAMMATION PHENOTYPE HAVE DIFFERENT SUBSETS OF THE MEC LAR SIGNATURES. -- MOLECULAR SIGNATURES. WHAT THE FIELD IS MISSING IS THE UNIFIED UNDERSTANDING OF THE PATHWAYS TOGETHER. IT'S NOT GOING TO BE A SIMPLE ANSWER. EVERY NEWS ARTICLE WE SEE IS LIKE AHA, X UNDER LIE THE DISORDER AND THE SIGNATURES ARE OFTEN DOWN STREAM OF THE EARLY TRIGGERS. WE HAVE TO ACCEPT THERE'S TRAUMATIC INTERPLAY BETWEEN THE BEHAVIORAL FACTORS OF RESILIENCE STUDIED FOR DECADES NOW. THE MOLECULAR AFFECTS OF BEHAVIORAL DIFFERENCES IN EARLY LIFE DIFFERENCES IN ENRICHMENT IN THE EXPERIENTIAL FACTORS ARE DRAMATICALLY DIFFERENT BETWEEN DIFFERENT SOCIO ECONOMIC AND DIFFERENT ETHNIC BACKGROUNDS IN OUR SOCIETY ARE HAVING AN ENORMOUS AFFECT ON ALZHEIMER'S DISEASE AND EVEN IN MICE WE FIND EARLY IN LIFE THERE'S A DRAMATIC IMPACT ON LATE LIFE SYNDROMES. SO UNDERSTANDING THIS BACK AND FORTH BETWEEN THE MOLECULAR SIGNATURES AND GENETIC SIGNATURES A LOT OF PHARMACEUTICAL DEVELOPMENT IS FOCUSSED ON AND HOW TO MODULATE THESE PATHWAYS AT THE DIFFERENT LEVELS AND EPIGENETIC AND METABOLOMIC LEVELS SO FORTH AND THESE ARE INTERFERED WITH EXPERIENTIAL AFFECTS IN COGNITIVE WAYS. WE'RE MISSING MAYBE A HOLISTIC VIEW OF ALZHEIMER'S TO UNDERSTAND HOW THE PATHOLOGY OF MOLECULAR SIGNATURES RELATE TO EACH OTHER AND HOW TO THINK ABOUT TREATMENT IN A VERY INDIVIDUALIZED WAY IN A WAY THAT DEALS WITH SEX DIFFERENCES. DEALS WITH ETHNIC BACKGROUND DIFFERENCES, SOCIO ECONOMIC DIFFERENCES AND SO FORTH. UNDERSTAND THE INTERRELATIONSHIP BETWEEN THE PATHWAYS. WE TALKED ABOUT MICROGLIA AND DENDROCYTES AND ASTROCYTES AND THEY ALL HAVE MAJOR ROLES AND WE CAN WRITE PAPER AND NEWS ARTICLE AFTER ARTICLE AND THEY ALL AFFECT AND ALL INTERACT WITH EACH OTHER. THAT'S WHERE THE FIELD NEEDS TO GO TO UNDERSTAND THAT INTERPLAY AND HOW TO USE MUTE -- MULTIFACETED FEATURES. >> I KNOW WE'RE RUNNING SHORT ON TIME SO ONE MORE QUESTION FOR DR. LEVINE. SINCE STUDYING THE AGING BRAIN AND CELLS IS IMPORTANT FOR UNDERSTANDING ALZHEIMER'S DISEASE, CAN YOU TALK MORE ABOUT HOW WE SHOULD APPROACH DEVELOPING IN VITRO AGING CELL MOELDZ AND YOU HAD MENTIONED AST ASTROCY ASTROCYTES, CAN YOU TALK ABOUT MICROGLIA AND ADENDROCYTES. >> THE WAY TO START TO UNRAVEL THAT IS TO DEVELOP THE IN VITRO CELL MODELS. WE'VE DONE THIS SO FAR WITH ASTROCYTES AND DOING IT AND WE'RE EXCITED TO SEE WHAT WE CAN INDUE -- INDUCE AS CHANGES AND RECAPITULATES AND WE LOOKED AT MOUSE MODELS AND TISSUES AND WE TALKED ABOUT WHAT WE'RE SEEING IN THE BRAIN. WE THINK THIS IS HOPE FOR AN EXCITING AVENUE TO START GETTING US THE MECHANISMS IN THE FUTURE MAYBE IT WILL SHED LIGHT ON TARGETING THEM EARLIER IN THE PROCESS. >> GREAT. ONE MORE QUESTION. THIS IS FOR CATHERINE. IN LIGHT OF THE TALKS IN THE SESSION, HOW MIGHT WE LEVERAGE UNIQUE STRAINS OF MOUSE MODELLING TO RESEARCH METABOLIC CONTRIBUTIONS TO AD RISK AND OTHERS AND EXPEDITE TRANSLATION OF DISCOVERIES IN MOUSE TO CLINICAL POPULATIONS? >> THAT IS A REALLY GREAT QUESTION. SO I THINK THAT ONE OF THE MAJOR GAPS CURRENTLY HAS BEEN TRANSLATING A LOT OF THE PROTEIN CELLULAR INTERACTIONS TO REALLY PURSUE FUNCTION AND SO UNCLASSICALLY TRAINED NEUROSCIENTISTS THERE'S A WEALTH OF KNOWLEDGE ABOUT HOW IMPORTANT NEURONS ARE FOR ENCODING AND STORING INFORMATION. SO I THINK THAT HAVING TOOLS THAT ALLOW US TO IDENTIFY THE PROTEINS BEING RELEASED FROM ASTRO GLIA TO LOOK AT NEURONAL EXCITABILITY AND EVEN RELATING THINGS LIKE RECEPTOR DENSITY AND OTHERS A LOT OF THE PROTEIN ABUNDANCES ARE NOT REALLY PICKED UP THROUGH BULK PROTEOMICS DATA. TOOLS THAT ALLOW US TO DO CELL TYPE SPECIFIC PROTEOMICS IN THE CONTEXT OF CELL TYPE DIVERSITY WOULD BE REALLY POWERFUL. I WOULD ALSO SAY ONE OF THE THINGS THAT WE THOUGHT HARD ABOUT WHEN WE DESIGNED THE AD BXDs WAS THE FACT THERE'S GENETICALLY DEVELOPED TOOLS AND BY HAVING THE FEMALE BACKGROUND WITH THE TRANSGENE OR ANY OTHER VARIANT YOU PUT IN THERE TO MAKE AN F1 POPULATION MAKES IT EASY TO INTEGRATE THE NEW TOOLS PEOPLE ARE DEVELOPING INCLUDING THE GENETICALLY CODED DYES. AND NATHAN'S SYSTEMS PHYSIOLOGY MODELS WE PROBABLY BENEFIT FROM THE INCORPORATION OF NEURONAL AND CIRCUIT FUNCTION IN THE CONTEXT OF COGNITIVE AGING AND AD. I THINK HIGH THROUGHPUT FUNCTIONAL IMAGING IN THE BRAIN. >> WE'RE GOING TO END ON TIME AND DIDN'T GET THROUGH ALL THE QUESTIONS WHICH IS A TESTIMONY TO THE EXCITEMENT IN THE FIELD AND THERE'S MORE QUESTIONS WE COULDN'T GET TO. I URGE PEOPLE IN THE AUDIENCE TO TRACK DOWN INDIVIDUAL SPEAKERS' E-MAIL AND SEND YOUR QUESTION DIRECTLY AND ENGAGE IN A CONVERSATION THAT WILL HOPEFULLY CONTINUE. I WANT TO THANK THE SPEAKERS AND MY CO-CHAIR AND THANK AGAIN NIA FOR PUTTING THIS SUMMIT TOGETHER AND FOR ALL THE WORK THEY'VE DONE ON BEHALF OF US AND ALL THE STAKEHOLDERS FOR AD, AD RD. THE FABULOUS PLENARY TALKS TO SET THE TONE FOR THIS MEETING. SO LET ME TURN IT OVER TO CATHERINE FOR THE FINAL WORDS. >> WHAT'S LEFT AFTER THAT, DAVID? YEAH, I THINK I WANT TO THANK DAVID FOR BEING AN AMAZING CO-CHAIR. HE'S REALLY PUSHED ME OUT OF MY COMFORT ZONE AND EVERY TIME HE'S ASKED ME SOMETHING, HE'S PUSHED BACK TO DO IT. IT'S BEEN A FUN OPPORTUNITY TO BE PART OF THIS SESSION AND SO I WANTED TO THANK DAVID. I ABSOLUTELY WANTED TO THANK ERICA AND SUSANA AND LAURIE FOR SPENDING A LOT OF TIME PREPARING AND ORGANIZING THIS SESSION. OF COURSE THE SPEAKERS WERE AMAZING. I FOLLOWED YOUR WORK FOR A LONG TIME AND CONTINUES TO GET BETTER AND BETTER. THE ATTENDEES AND EVERYBODY, I HOPE YOU LOOK FORWARD TO AN AMAZING DAY PLANNED TOMORROW. HAVE A GREAT AFTERNOON.