>> HUMAN GENOME RESEARCH
INSTITUTE AND STILL AN ACTIVE
PHYSICIAN SCIENTIST IN THE
INTRAMURAL PROGRAM OF NHGRI.
AND IT IS MY ENORMOUS PLEASURE
TO WELCOME YOU TODAY TO THE
TENTH INSTALLMENT IN THE 2024
SEASON OF DEMYSTIFYING MEDICINE,
A COURSE THAT'S BEEN GOING ON
FOR A NUMBER OF YEARS, OVER 20,
I BELIEVE, THAT AIMS TO BRIDGE
THE EXCITING DEVELOPMENTS IN
BIOLOGY AND ENGINEERING WITH
MEDICINE.
AND OF COURSE WE HAVE THE ICONIC
PICTURE OF THE BROOKLYN BRIDGE.
LET'S SEE.
OH, MY GOODNESS.
I WENT TOO FAR FORWARD -- OF THE
BROOKLYN BRIDGE HERE.
IN THE UPPER RIGHT-HAND CORNER.
WHICH IS OF COURSE BRIDGING
MANHATTAN WITH BROOKLYN OF ALL
PLACES OVER THE EAST RIVER, AND
YOU CAN SEE IN THE LEFT-HAND
SIDE OF THE PHOTO THAT THERE ARE
THESE TWO GUYS, ONE OF THEM FROM
MAMANHATTAN, THE OTHER FROM
BROOKLYN, THAT ARE HAVING A VERY
HEATED CONVERSATION ABOUT ONE OF
THE SCIENTIFIC TOPICS OF
INTEREST OF THE DAY BACK IN THE
1870s, AND WE HOPE TO ENGENDER
THAT SAME KIND OF FERVENT
DISCUSSION BETWEEN OUR TWO
PRESENTERS, DR. SONJA SCHOLZ,
AND DR. REBECCA GOTTESMAN, WHO
WILL BE TALKING TO US TODAY
ABOUT DEMENTIA, BOTH THE GENETIC
AND VASCULAR FACTORS
PREDISPOSING TO DEMENTIA.
IN ANY CASE, AND SO WE HOPE WE
WILL HAVE A LIVELY DISCUSSION, A
LIVELY PRESENTATIONS, WE'LL HEAR
THE TWO PRESENTATIONS AND THEN
QUESTION AND ANSWER AT THE END
AND WE'LL GO ON AT LEAST UNTIL
6:00 AND IF THERE'S STILL MORE
QUESTIONS, WE'LL TAKE THEM BY
EMAIL.
WE WANT TO BREAK DOWN THE SILOS
AS YOU SEE IN THE LOWER
RIGHT-HAND CORNER, PERHAPS EVEN
WITH A FEW CORNY JOKES.
SO IN ANY CASE, THIS IS A SERIES
THAT GOES ON FROM JANUARY UNTIL
MAY OF 2024.
YOU CAN WATCH IT AT THE LINK
SHOWN THERE ON THIS FIRST SLIDE
THAT YOU CAN GET CME CREDITS IF
YOU JUST PUT IN THE CODE 52095.
IF YOU HAVE QUESTIONS, YOU CAN
USE THE SEND LIVE FEEDBACK
BUTTON ON THE VIDEOCAST DISPLAY.
ALL OF THE PREVIOUS SESSIONS ARE
ARCHIVED AND THIS ONE WILL BE
TOO, AND IF YOU HAVE QUESTIONS
YOU CAN USE THAT EMAIL ADDRESS
THERE FOR ADDITIONAL
INFORMATION.
THIS SLIDE JUST GIVES YOU MORE
INFORMATION ABOUT CME.
WE WON'T BELABOR IT ACCEPT AGAIN
THE CODE, 52095.
AND JUST IN TERMS OF SPEAKER
DISCLOSURES, SCHOLZ HAS REPORTED
GRANT OR RESEARCH REPORT FROM
CERAVEL THERAPEUTICS.
IN ANY CASE, LET'S GET ON WITH
IT.
SO OUR TALK TODAY, OUR TALKS
TODAY ARE ON COGNITIVE LOSS,
DEMENTIA, AND NEURODEGENERATIVE
DISORDERS.
BOTH THE VASCULAR AND GENETIC
FACTORS THAT PREDISPOSE TO THEM
AND OUR FIRST SPEAKER WHO WILL
BE SPEAKING IN PERSON WILL BE
DR. SONJA SCHOLZ.
AND SHE IS A LASKER CLINICAL
RESEARCH SCHOLAR AND CHIEF OF
THE NEURODEGENERATIVE DISEASES
RESEARCH UNIT AT THE LABORATORY
OF NEUROGENETICS AT THE NATIONAL
INSTITUTE FOR NEUROLOGIC
DISORDERS AND STROKE, THE NINDS.
SHE GOT HER MEDICAL DEGREE FROM
THE MEDICAL UNIVERSITY OF INN
INNSBRUCK IN AUSTRIA, SHE THEN
DID A POSTDOCTORAL FELLOWSHIP AT
THE LABORATORY OF NEUROGENETICS
AT THE NATIONAL AGING INSTITUTE,
WITH ANDY SINGLETON AND JOHN
HARDY, AND DID A NEUROLOGY
RESIDENCY AND CHIEF RESIDENCY AT
JOHNS HOPKINS.
AND SHE IS ALSO THE RECIPIENT OF
THE MCFARLAND TRANSITION TO
INDEPENDENCE AWARD FOR
NEUROLOGIST SCIENTISTS.
HER LABORATORY RESEARCH GROUP
APPLIES GENOMIC TECHNIQUES TO
LEWY BODY DEMENTIA, MULTIPLE
SYSTEM ATROPHY, FRONTOTEMPORAL
DEMENTIA, PROGRESSIVE
SUPRANUCLEAR PALSY AND
CORTICOBASAL DEGENERATION.
UNRAVELING MOLECULAR MECHANISMS
AND IDENTIFYING TARGETS FOR DRUG
DEVELOPMENT.
OUR SECOND SPEAKER IS
DR. REBECCA GOTTESMAN.
SHE WILL BE SPEAKING TO US
REMOTELY TODAY.
AND SHE IS THE CHIEF OF THE
STROKE, COGNITION AND
NEUROEPIDEMIOLOGY SECTION AND
THE STROKE BRANCH OF THE
NATIONAL INSTITUTE OF NEUROLOGIC
DISORDERS AND STROKE, THE NINDS.
SHE GOT HER MD, MAGNA CUM LAUDE,
FROM COLUMBIA UNIVERSITY COLLEGE
OF PHYSICIANS AND SURGEONS.
SHE RECEIVED A PH.D. IN CLINICAL
INVESTIGATION FROM JOHNS HOPKINS
BLOOMBERG SCHOOL OF PUBLIC
HEALTH, DID A NEUROLOGY
RESIDENCY AND VASCULAR NEUROLOGY
FELLOWSHIP AT JOHNS HOPKINS, AND
BEFORE COMING TO THE NIH, WAS A
PROFESSOR OF NEUROLOGY AND
EPIDEMIOLOGY AT JOHNS HOPKINS.
SHE'S AN ELECTED MEMBER OF THE
AMERICAN SOCIETY OF CLINICAL
INVESTIGATION.
AND HER RESEARCH GROUP THROUGH
LARGE EPIDEMIOLOGIC COHORTS,
STUDIES THE ASSOCIATION BETWEEN
VASCULAR RISK FACTORS,
ESPECIALLY IN MID LIFE, AND
COGNITIVE DECLINE AND DEMENTIA.
AND AS A PART OF A LARGE COHORT
STUDY, THEY'RE CURRENTLY
RECRUITING PATIENTS WITH STROKE
ACROSS 30 U.S. SITES, EVALUATING
THE ASSOCIATION BETWEEN STROKE
AND DEMENTIA, AND THEY LOOK AT
RISK FACTORS FOR PROGRESSION OF
AND OUTCOMES RELATED TO CEREBRAL
SMALL VESSEL DISEASE.
WELL, WITH ALL THAT HAVING BEEN
SAID, IT'S TIME TO GET ON WITH
THINGS AND INVITE DR SCHOLZ TO E
UP TO THE PODIUM AND RE GA REGAS
WITH STORIES OF GENETIC FACTORS
THAT PREDISPOSE TO DEMENTIA.
SCHOLZ, TAKE IT AWAY.
>> THANK YOU VERY MUCH FOR THE
KIND INTRODUCTION, AND THANK YOU
FOR HAVING ME TODAY, FOR
ALLOWING ME TO SPEAK ABOUT AN
EXCITING AND EMERGING FIELD, HOW
GENETIC FACTORS AND VASCULAR
FACTORS ARE ACTUALLY PLAYING A
COAL IN COGNITIVE DECLINE AND
DEMENTIA.
BEFORE I GET STARTED HERE ARE MY
DISCLOSURES THAT HAVE ALREADY
BEEN HIGHLIGHTED.
I AM AN INTRAMURAL RESEARCHER
AND RECEIVED SOME INDUSTRY
SUPPORT AND ALSO SERVE ON VEFERL
BOARDS, ADVISORY AND EDITORIAL
BOARDS.
SO THE TOPICS THAT WE'RE GOING
TO COVER TODAY ARE IF FIELDS WE
COLLECTIVELY SUMMARIZE AS
NON-ALZHEIMER'S DEMENTIAS.
I'M GOING TO GO INTO THAT TERM,
WHAT WE SPECIFICALLY MEAN AMINO
BYTHAT AND WE DELIBERATELY CHOSE
THAT BECAUSE WHEN WE TALK ABOUT
DEMENTIA, WE OFTEN FOCUS ON
ALZHEIMER'S DISEASE BUT WE
REALLY WANT TO CONVEY THERE'S A
WHOLE GROUP OF DISEASES THAT ARE
UNDERLYING DEMENTIA SYNDROMES
AND IT'S ACTUALLY BY STUDYING
THE BROADER SPECTRUM WE CAN
REALLY LEARN A LOT ABOUT
NEUROLOGIC DISEASES OF AGING.
SO MY JOB AS THE FIRST SPEAKER
IS TO REALLY FOCUS IN ON THE
NEURODEGENERATIVE FORMS OF
DEMENTIAS INCLUDING LUO BODY AND
FRONTOTEMPORAL DEMENTIA AND I'LL
SHOWCASE A COUPLE EXAMPLES FROM
MY LAB AND HOW WE USE GENOMIC
TOOLS TO PINPOINT DISEASE
MECHANISMS AND CHANGES THAT MAY
BE TRANSLATIONAL BILLY RELEVANTD
IN THE SECOND HALF,
DR. GOTTESMAN IS THEN GOING TO
LOOK AT VASCULAR FACTORS AND
REVIEW WITH US HOW THESE
VASCULAR CONTRIBUTIONS ARE
PLAYING A ROLE IN COGNITIVE
DECLINE AND DEMENTIA.
THEN WE BRING IT ALL TOGETHER
AND REALLY DISCUSS HOW THEY
ACTUALLY LINK TOGETHER, HOW
VASCULAR FACTORS ARE PLAYING AN
IMPORTANT ROLE IN
NEURODEGENERATION, WHAT DOES IT
MEAN MOVING FORWARD.
ALL RIGHT.
LET'S JUST START OUT WITH GIVING
A LITTLE BIT OF BACKGROUND
INFORMATION.
SO IT DOESN'T COME AS A SURPRISE
THAT WE ARE AN AGING SOCIETY.
AS A COMMUNITY, WE'RE ENJOYING
LONGER LIFE EXPECTANCIES DUE TO
JUST DRASTIC CHANGES IN MEDICAL
CARE BUT ALSO PUBLIC HEALTH
MEASURES, AND WHILE THAT IS, OF
COURSE, GREAT NEWS, IT ALSO
COMES WITH ITS OWN CHALLENGES.
SO AS A SOCIETY, WE'LL HAVE TO
ADAPT AS TO HOW WE ARE GOING TO
DELIVER HEALTHCARE FOR AN
INCREASINGLY AGING POPULATION.
SO THESE DEMOGRAPHIC CHANGES
REALLY ARE COMING TO US RATHER
RAPIDLY.
WE ACTUALLY HAVE TO DEAL WITH
AGE-RELATED NEURODEGENERATIVE
DISEASES AND STROKES AT SUCH A
RAPID PACE THAT IT'S REALLY
DIFFICULT FOR US TO JUST KEEP UP
WITH THE PATIENT VOLUME.
SO THE NEUROLOGICAL DISEASES
THAT ARE ASSOCIATED WITH AGING
ARE REALLY A MAJOR CHALLENGE.
SO SHOWN HERE ARE -- OKAY.
SO SHOWN HERE ARE -- I HOPE YOU
CAN HEAR ME.
SO SHOWN HERE ARE THE
NEUROLOGICAL DISEASES ACROSS THE
LIFESPAN.
SO IN EARLY CHILDHOOD, THE
NEUROLOGICAL CONDITIONS WE
MOSTLY DEAL WITH ARE INFECTIOUS
DISEASES, THEN IN ADOLESCENCE,
YOUNG ADULTHOOD IT'S MORE
HEADACHE SYNDROMES, AUTOIMMUNE
CONDITIONS, BUT AS WE ARE
GETTING OLDER, STROKE AND
DEMENTIA SYNDROMES ARE A REAL
CHALLENGE.
AND IT IS NOT SURPRISING THAT
THEY ARE ACTUALLY MAJOR CAUSES
OF DEATH IN THE POPULATION OVER
65, ALSO MAJOR CAUSES OF
DISABILITY, AND THAT'S REALLY
CONCERNING.
AND AS A HEALTHCARE COMMUNITY,
WE ARE REALLY CALLED TO ACTION
TO ACTUALLY TACKLE THIS PROBLEM.
SO HERE ARE SOME IMPORTANT
NUMBERS.
DEMENTIA ON A WORLDWIDE SCALE IS
A MASSIVE PROBLEM, ABOUT
55 MILLION PEOPLE ARE SUFFERING
FROM DEMENTIA, AND ABOUT
7 MILLION OF THOSE ARE JUST IN
THE UNITED STATES.
THIS IS PROJECTED TO GROW VERY
DRAMATICALLY IN THE NEXT FEW
DECADES BECAUSE OF THE
DEMOGRAPHIC CHANGES AND
PARTICULARLY WHAT'S HAPPENING IN
LOW AND MIDDLE INCOME COUNTRIES.
AND THE CURRENT COST IS ABOUT
$1.3 TRILLION ALREADY, BY 2030
IT'S GOING TO BE $2.8 TRILLION,
SO WE'RE GETTING TO A POINT
WHERE IT'S JUST
SOCIOECONOMICALLY NOT VIABLE,
AND THAT'S WHY WE NEED TO
UNDERSTAND THIS DISEASE AND COME
UP WITH TREATMENTS VERY RAPIDLY.
AS I SAID, DEMENTIA SYNDROMES
ARE REALLY IMPORTANT IN THE
AGING POPULATION, AND WHILE
ALZHEIMER'S DISEASE IS THE MOST
COMMON FORM OF DEMENTIA, THERE'S
A WHOLE GROUP OF OTHER DISEASES,
WHICH WE ELECTIVELY DESCRIBE AS
THE NON-ALZHEIMER'S DEMENTIAS,
OR RELATED DEMENTIAS.
THEY INCLUDE VASCULAR DEMENTIA,
WHICH IS THE TO PICK TOPIC OF S
TALK.
WHAT DO WE ACTUALLY MEAN WITH
THIS TERM DEMENTIA?
SO IT'S A CLINICAL TERM, AND IT
BASICALLY IS DEFINED AS HAVING
SIGNIFICANT COGNITIVE DECLINE IN
AT LEAST TWO OR MORE DOMAINS.
IT HAS TO BE SEVERE ENOUGH TO
INTERFERE WITH INDEPENDENCE OF
DAILY LIVING.
SO THOSE ARE ACTIVITIES SUCH AS
BATHING YOURSELF, FEEDING
YOURSELF, MANAGING BASIC
HYGIENE.
SO YOU HAVE TO BE REALLY
IMPAIRED IN ORDER TO QUALIFY FOR
THE CLINICAL DIAGNOSIS OF
DEMENTIA.
WHAT WE MEAN WITH COGNITIVE
DOMAINS ARE HIGHER COGNITIVE
FUNCTIONS SUCH AS BEING ABLE TO
FORM MEMORIES, BEING ABLE TO
ORIENT YOURSELF IN SPACE AND
INTEGRATE VISUAL INFORMATION
INTO MEANINGFUL CONCEPTS, BEING
ABLE TO FORMULATE THOUGHTS,
BEING ABLE TO PAY ATTENTION TO
THOUGHTS, ORGANIZE YOUR
THOUGHTS, EXECUTIVE FUNCTION,
BUT ALSO BEHAVIOR IN THE
GENERATION AND PRODUCTION OF
LANGUAGE AND COMPREHENSION OF
LANGUAGE, ALL HIGHER COGNITIVE
DOMAINS.
AND YOU CAN IMAGINE DEPENDING ON
THE UNDERLYING DISEASE PROCESS,
THERE MAY BE DIFFERENT PATTERNS
OF COGNITIVE IMPAIRMENT THAT WE
CAN SEE.
SO IN ALZHEIMER'S DISEASE, WHICH
IS OUR TEXTBOOK EXAMPLE, IN ITS
MOST DIFFICULT PRESENTATION, YOU
GET IMPAIRMENT OF SHORT TERM
MEMORY, BUT YOU ALSO HAVE
DIFFICULTIES WITH VISUAL
PERCEPTUAL VISUAL SPAISHT
FUNCTION, GETTING LOST IN
FAMILIAR ENVIRONMENTS, HAVING
DIFFICULTIES WITH RECALLING
NAMES, KIND OF TIP OF THE TONGUE
FEELING, THAT'S THE TYPICAL
PRESENTATION OF ALZHEIMER'S
DISEASE.
IIN LILEWY BODY DEMENTIA PATIENS
MANIFEST WITH VISUAL
HALLUCINATIONS THAT ARE VERY
WELL FORMED BUT ALSO EXECUTIVE
FUNCTION PROBLEMS SUCH AS
IMPAIRED WORKING MEMORY,
IMPAIRED INTENTIONAL TASKS THAT
OFTEN CAN FLUCTUATE FROM HOUR TO
HOUR OR FROM DAY TO DAY.
IN ADDITION, THESE PATIENTS ALSO
OFTEN HAVE PARKINSON
DISEASE-LIKE SYMPTOMS, BEING
STIFF, BEING SLOW.
SO IT'S A DIFFERENT PATTERN YOU
CAN RECOGNIZE AND YOU REALLY
LOOK FOR IMPAIRMENTS IN THESE
DOMAINS IN ORDER TO MAKE A
CLINICAL DIAGNOSIS.
AND THE THIRD MAJOR GROUP ARE
THE FRONTOTEMPORAL DEMENTIA
SYNDROMES.
IT'S ACTUALLY A COUPLE OF
DISEASES SUMMARIZED UNDER THAT
UMBRELLA TERM.
THERE ARE DIFFERENT SUBTYPES.
ONE SUBTYPE AFFECTS BEHAVIOR
PREDOMINANTLY, ANOTHER AFFECTS
PREDOMINANTLY LANGUAGE BUT THERE
IS OFTEN A LOT OF OVERLAP.
SO YOU CAN SEE THERE ARE
DIFFERENT PATTERNS JUST IN THE
CLINICAL PRESENTATION.
SO ASIDE FROM HAVING ONGOING
PROGRESSIVE NEUROLOGICAL
DECLINE, THE OTHER MAJOR
HALLMARKER OF NEURODEGENERATION
IS THE DEPOSITION OF SPECIFIC
PROTEINS.
IN ALZHEIMER'S DISEASE, THE
PROTEINS THAT WE FIND DEPOSITED
IN THE BRAINS OF PATIENTS ARE
SO-CALLED BETA AMYLOID IN THE
FORM OF AMYLOID PLAQUES.
AND TAU PROTEIN, TANGLES, TO
ESTABLISH A PATHOLOGICAL
DIAGNOSE.
LEWY BODY DEMENTIA DISEASE WHERE
WE SEE ABNORMAL DEPOSITION OF
MISFOLDED ALPHA SYNUCLEIN
PROTEIN IN THE FORM OF SO-CALLED
LEWY BODIES, HENCE THE DISEASE
NAME.
FRONTOTEMPORAL DEMENTIA ON THE
OTHER HAND IS USUALLY A DISEASE
OF EITHER DEPOSITION OF TDP
TDP-43 PROTEIN OR TAU.
THEALTHOUGH THIS LOOKS NICE AND
CLEAN, THIS SCHEMA IS A VERY
IDEAL WORLD.
IN REALITY, WE HAVE LEARNED THAT
THERE ARE TREMENDOUS OVERLAPS
ACROSS THE DISEASE ENTITIES.
LEWY BODY EMBODIES THAT, WHEN WE
LOOK AT PATIENTS WITH LEWY BODY
DEMENTIA, WE SEE 80% OF PATIENTS
ALSO HAVE SIGNIFICANT
ALZHEIMER'S DISEASE
CO-PATHOLOGY.
IT'S NOT SURPRISING THAT WHEN WE
GO AND LOOK AT THE GENETICS, WE
ACTUALLY SEE A LOT OF OVERLAPS
IN THE GENETIC RISK PROFILES.
AND WHILE IT'S MAKING OUR LIVES
A LITTLE BIT MORE DIFFICULT,
IT'S ACTUALLY GOOD NEWS BECAUSE
IT SUGGESTS THAT A LOT OF THE
INSIGHTS WE GAIN IN ONE FIELD
COULD HAVE IMPLICATIONS IN A
MUCH BROADER SPECTRUM OF
NEURODEGENERATIVE DISEASING.
AND THERE ARE OTHER EXAMPLES.
WE ALSO SEE, FOR EXAMPLE, TDP-4A
SUBSTANTIAL PROPORTION OF
ALZHEIMER'S DISEASE LEWY BODY
DEMENTIA CASES AND VICE VERSA.
SO WE'RE STILL LEARNING HOW TO
BEST APPROACH THAT.
IT'S REALLY A SPECTRUM OF
CONDITIONS THAT WE'RE TRYING TO
STUDY.
HERE'S JUST A VERY FAMOUS STUDY
THAT'S RUN OUT OF RUSH
UNIVERSITY WHERE THEY BASICALLY
LOOKED AT ALZHEIMER'S DISEASE,
WE THINK WE KNOW HOW TO DIAGNOSE
THESE CASES, LOOK AT THE
PATHOLOGY YOU CAN FIND IN THESE
INDIVIDUALS.
ACTUALLY ONLY A SMALL FRACTION
OF THE INDIVIDUALS WITH PROBABLE
ALZHEIMER'S DISEASE ON PATHOLOGY
HAVE PURE ALZHEIMER'S DISEASE
PATHOLOGY CHANGES.
THE VAST MAJORITY ACTUALLY HAVE
ALL SORTS OF CO-PATHOLOGIES.
VASCULAR DISEASE ON TOP OR IN
MOST INSTANCES, ALZHEIMER'S
DISEASE PLUS OTHER DEGENERATIVE
CHANGES SUCH AS LEWY BODYs,
TDP-43, VASCULAR DISEASE, SO
THERE'S REALLY TREMENDOUS
OVERLAP ACROSS THESE DISEASES.
SO THAT'S AN IMPORTANT POINT TO
WRAP OUR MINDS AROUND.
THESE DISEASES ARE NOT BLACK AND
WHITE ENTITIES AS WE LIKE TO
PRESENT THEM.
THIS IS WHERE GENETICS CAN
ACTUALLY BE QUITE ELEGANT.
SO WE LOVE COMPLEX DISEASES.
WE HAVE AN ENTIRE FIELD CALLED
COMPLEX GENETICS WHERE WE REALLY
TRY TO TEASE APART HOW MOLECULAR
FACTORS ARE PLAYING A ROLE.
IN DEMENTIA, WE KNOW GENETIC
FACTORS ARE INVOLVED.
IN SOME INSTANCES, WE DO SEE
CLEAR FAMILY HISTORIES.
IT'S USUALLY JUST SMALL
PROPORTION IN ALZHEIMER'S
DISEASE.
IT'S REALLY ABOUT 10% OF
PATIENTS, FRONTOTEMPORAL
DEMENTIA, ABOUT 40% OF PATIENTS
WHO HAVE A CLEAR FAMILY HISTORY.
BUT EVEN IN THOSE APPARENTLY
SPORADIC CASES, ONCE WE START
LOOKING AT GENETIC FACTORS, WE
DO FIND RISK GENES INVOLVED THAT
ARE PREDISPOSING INDIVIDUALS TO
DEVELOP THE DISEASE.
SO I'M GOING TO SHOW YOU SOME
EXAMPLES OF HOW WE HAVE BEEN
LEVERAGING MODERN GENOMIC TOOLS
TO PINPOINT WHERE THE PROBLEMS
ARE, WHERE THE PATHWAYS AND HOW
CAN WE USE TO SHOW THE
RELATIONSHIPS BETWEEN THESE
DISEASE ENTITIES.
SO MY LAB IS REALLY FOCUSING
VERY HEAVILY ON LEWY BODY
DEMENTIA, WHICH IS THE SECOND
MOST COMMON NEURODEGENERATIVE
DEMENTIA TO ALZHEIMER'S DISEASE,
CHARACTERIZED BY A COMPLEX
NEUROPSYCHIATRIC SYNDROME, AND
THESE VERY CLASSICAL LEWY BODIES
MADE UP OF ALPHA SYNUCLEIN
PROTEIN.
ABOUT A THIRD OF ALL PATIENTS
ACTUALLY HAVE A FAMILY HISTORY
OF DEMENTIA OR PARKINSON'S
DISEASE IN FIRST OR
SECOND DEGREE RELATIVES AND
THAT'S REALLY VERY SUSPICIOUS.
LUCKILY, WE LIVE IN THE MODERN
AGE.
WE LIVE IN THE GENOMICS ERA, SO
WHEN I STARTED OFF MY LAB, I
IMMEDIATELY REALLY WENT FOR NEXT
GENERATION SEQUENCING
APPLICATIONS BECAUSE WE CAN NOW
READ THE GENETIC INFORMATION AT
SUCH AN ADVANCED CASE THAT WE
CAN ACTUALLY PINPOINT VARIANTS
IN RECORD TIME.
AND SO I WANT TO JUST REVIEW
WHAT THE KIND OF APPROACHES ARE
THAT WE ARE USING IN GENETICS.
SO IF WE HAVE FAMILIES, WE
TYPICALLY LIKE TO USE SO-CA
SO-CALLED -- WE LOOK FOR
MUTATIONS THAT OCCUR IN THE
FAMILIES AND THAT SEG GREAT WITH
THE DISEASE.
THIS TOOL HAS BEEN SUPER
SUCCESSFUL IN THE PEDIATRIC
COMMUNITY WHERE WE HAVE LOTS OF
FAMILY MEMBERS THAT MAY BE
AFFECTED.
HOWEVER, IN OUR AGED COMMUNITY,
THIS HAS REALLY BEEN DIFFICULT.
WE MAY HAVE FAMILY HISTORIES BUT
WE OFTEN DO NOT HAVE MULTIPLE
GENERATIONS ALIVE.
SO OUR MAIN WORKHORSE, SO TO
SPEAK, ARE ASSOCIATION STUDY
TESTS.
SO ASSOCIATION STUDIES ARE
BASICALLY COMPARING LARGE
COHORTS OF CASES VERSUS
CONTROLS, AND WE CAN BASICALLY
LOOK FOR DIFFERENCES IN THEM,
EITHER AT A GENE LEVEL OR
GENOME-WIDE IDEA MAYBE BECAUSE
THEN WE CAN DO UNBIASED
GENOME-WIDE SCREENING.
SO THIS IS A PLOT THAT WE
GENETICISTS JUST LOVE TO SHOW.
IT'S NAMED AFTER NHGRI
INVESTIGATOR TERRY WHO FIRST
SHOWED THAT.
IT BASICALLY ENCAPSULATES HOW WE
THINK ABOUT A COMPLEX GENETIC
DISEASE SUCH AS A DEMENTIA
SYNDROME WHERE WE HAVE A SMALL
SUBSEGMENT OF THE PATIENT
POPULATION THAT HAS -- WE WANT
TO USE A STATISTICAL TOOL CALLED
LINKAGE ANALYSIS.
HOWEVER, THE MOST PATIENTS THAT
WE SEE, THEY HAVE APPARENTLY
SPORADIC DISEASE, AND FOR THOSE
WE'RE USING A TOOL CALLED GENOME
WIDE ASSOCIATION STUDIES, WHERE
WE TEST MILLIONS OF VARIANTS
ACROSS THE ENTIRE GENOME AND
LOOK FOR SIGNIFICANT DIFFERENCES
IN THE CASES VERSUS CONTROLS.
IN BETWEEN, WE HAVE ANOTHER TEST
THAT WE LIKE TO USE WHICH IS
KIND OF AN IN BETWEEN WHERE WE
HAVE A HYPOTHESIS IN MIND AND WE
CAN LOOK FOR AN ASSOCIATION.
SO FOR EXAMPLE, DO WE SEE
ENRICHMENT OF DAMAGING MUTATIONS
IN A CERTAIN PATHWAY OR IN A
CERTAIN GENE, AND THAT CAN HELP
US SEE IF THERE ARE ACTUAL
DISEASE RELATIONSHIPS.
BUT HAVING THAT SAID, ONCE WE
PINPOINT WHERE A PROBLEM IS, OUR
WORK ISN'T DONE AS GENETICISTS.
SO OVER THE LAST DECADE IN
PARTICULAR, THERE'S A WHOLE NEW
FIELD WHICH HAS EMERGED WHICH IS
CALL WOULD THE FUNCTIONAL
GENOMICS FIELD, WHERE WE
ESSENTIALLY TRY TO ADD
ADDITIONAL LAYERS OF OMIC
INFORMATION ON TOP OF THE
GENOME, SO FOR EXAMPLE, WE HAVE
RISK VARIANTS IN A CERTAIN AREA
OF THE GENOME THAT WE THINK ARE
INVOLVED BUT WE STILL DON'T KNOW
WHICH OF THE MANY VARIANTS IN
THERE ARE ACTUALLY DRIVING THE
DISEASE SUSCEPTIBILITY.
SO BY DOING STATISTICAL TESTS,
WE CAN LOOK AT WHICH TRANSCRIPTS
HAVE CHANGED, WHICH PROTEINS ARE
CHANGED, AND IN A WAY WE'RE
REALLY TRYING TO USE A SYSTEMS
BIOLOGY FRAMEWORK TO PIN POIT ..
WHAT ARE THE VARIANTS, WHAT ARE
THE POSSIBLE MECHANISMS AS TO
HOW IT'S RELATED TO DISEASE.
THIS SOUNDS SOMEWHAT SIMPLIFIED
BUT IT CAN HELP US REALLY WITH
PRIORITIZING WHICH VARIANTS
WE'RE GOING TO TEST IN A MODEL
SYSTEM, WHICH IS WHERE IT GETS
REALLY INVOLVED AND EXPENSIVE.
SO WE ARE USING A COHORT THAT WE
ESTABLISHED OVER THE LAST COUPLE
OF YEARS, AND I'M GOING TO JUST
VERY BRIEFLY HIGHLIGHT WHAT WENT
INTO THIS.
SO WE PERFORMED WHOLE GENOME
SEQUENCING IN ABOUT 2600 LEWY
BODY DEMENTIA CASES FROM ALL
ACROSS EUROPE, ALL ACROSS NORTH
AMERICA, WENT TO ALL SORTS OF
BRAIN BANKS WE COULD POSSIBLY
FIND, AND WE WERE REALLY
EMPHASIZING WELL CHARACTERIZED
CASES.
ABOUT 70% OF THE CASES WERE FROM
PATHOLOGIC CONFIRMED INDIVIDUALS
AND THE REMAINING CASES WERE
CLINICALLY PROBABLE DISEASE
CASES, REALLY CASES WHERE WE
WERE PRETTY SURE THAT'S THEIR
CLINICAL SYNDROME WE'RE TRYING
TO STUDY.
ALL OF THESE INDIVIDUALS WERE
GENOME SEQUENCED USING UNIFORM
PIPELINE AND UNIFORM VARIANT
CULLING, THEN WE WENT TO WORK.
WE PUT OUR GWAS APPROACH TO GOOD
USE HERE.
SO WHEN WE DID THAT, WE
IDENTIFIED THERE WERE FIVE MAJOR
RISK SIGNALS ASSOCIATED WITH
LEWY BODY DEMENTIA
SUSCEPTIBILITY.
SO THESE ARE GBA, SNCA, APOE,
BIN1 AND TMEM175.
THREE OF THOSE HAVE ALREADY BEEN
IMPLICATED BASED ON CANADA GENE
WORK, SO WE WERE REALLY
REASSURED TO SH SEE THEM SHOWINP
HERE.
-- IN PARKINSON DISEASE AND
ALZHEIMER'S DISEASE, AND NOW
WE'RE SEEING THEM SHOWING UP
HERE IN OUR LEWY BODY DEMENTIA
PATIENT POPULATION, WHICH REALLY
SUGGESTS THAT LEWY BODY DEMENTIA
PROBABLY SITS SOMEWHERE ALONG
THE SPECTRUM BETWEEN THESE TWO
DISEASES, AND THE GENETIC
ARCHITECTURES ARE LIKELY TO
OVERLAP.
SO THAT'S JUST A SIMPLIFIED
VIEW.
THIS IS JUST WITHOUT GOING INTO
THE DETAILS.
BUT I MENTIONED ONCE WE HAVE A
SIGNAL IN GWAS, WE CAN DELVE IN
FURTHER.
WE USED A TRANSCRIPTOMICS DATA
AND USED A SO-CALLED
COLOCALIZATION ANALYSIS.
IN DOING SO, WE WERE ABLE TO
REALLY HIGHLIGHT A FUNCTIONAL
VARIANT THAT SEEMS TO BE
AFFECTING THE EXPRESSION OF THIS
PROTEIN OF SNCA THAT ENCODES THE
ALPHA SYNUCLEIN PROTEIN.
SO THE TRANSCRIPT THAT SEEMS TO
REGULATE IT IS CALLED SNCA AS-#.
BAS-1.PARKINSON'S DISEASE, THE N
SIGNAL IS ACTUALLY COMING FROM
AN ENTRONIC SEQUENCE SO THERE'S
A DIFFERENCE ONCE YOU REALLY
START TO ZOOM IN.
BASED ON OUR EVALUATION, WHAT
OUR DATA SUGGESTS IS THAT THE
RISK IS -- ACTUALLY IT'S A
PROTECTIVE ONE, IF YOU HAVE THIS
RISK ALLELE, YOU ACTUALLY
PRODUCE A LITTLE BIT LESS OF
ALPHA SYNUCLEIN PROTEIN THAT'S
PROTECTIVE IN LEWY BODY
DEMENTIA.
THINKING THAT THROUGH, IT ALSO
SUGGESTS THAT BY LOWERING ALPHA
SYNUCLEIN, YOU MAY BE ABLE TO
PROTECT, YOU MAY HAVE A DISEASE
MODIFYING STRATEGY FOR PATIENTS
WITH LEWY BODY DEMENTIA.
SO THAT'S JUST ONE OF THE WAYS
WE ARE TRYING TO COMBINE GENETIC
SIGNALS WITH POSSIBLE FUNCTIONAL
EFFECTS.
NOW LOOKING AT A DIFFERENT
SEGMENT OF THE GENETIC ARCTIC
SURE, WE CAN ALSO LOOK AT
DAMAGING MUTATIONS THAT ARE RARE
BUT THAT ARE ENRICHED IN CERTAIN
GENES, AND SO THE WAY WE DID
THAT IS BY BASICALLY LOOKING ON
GENE-BASED GENE BURDEN TESTS
ACROSS THE ENTIRE GENOME, POWER
IS ALWAYS AN ISSUE BUT IF YOU
HAVE A REALLY COMMON RISK GENE,
YOU SEE SOMETHING.
WE WERE VERY LUCKY TO ACTUALLY
SEE THAT MUTATIONS, MISSENSE
MUTATIONS BUT ALSO LOSS OF
FUNCTION MUTATIONS IN THE GBA
GENE WHICH WE HAD SEEN IN THE
GWAS AS WELL ACTUALLY SHOWING
UP -- IT'S A MAJOR GENE, AND
ONCE YOU SEE THAT, WE REFER TO
IT AS PLEIOMORPHIC.
COMMON VARIANT AND YOU OFTEN
HAVE MORE RARE VARIANTS.
IN TOTAL WHEN WE SUM UP ALL OF
THE RISK ALLELE CARRIERS, WE SEE
IT IN ABOUT 13% OF PATIENTS WITH
LEWY BODY DEMENTIA, AND IT A
MAJOR RISK GENE FOR THIS
DISEASE, A MAJOR TARGET FOR
THERAPY DEVELOPMENTS.
AND SO THIS IS REALLY SOMETHING
THAT'S BEEN QUITE EXCITING AND
WE'RE GOING TO HEAR MORE ABOUT
THIS PARTICULAR GENE AS WE MOVE
FORWARD.
THE OTHER CONCEPT THAT I REALLY
WANTED TO INTRODUCE IS THE
CONCEPT OF POLYGENIC RISK.
SO UNLIKE MENDELIAN DISEASE
WHERE YOU HAVE ONE MAJOR DEFECT
THAT IS CAUSING A DISEASE,
POLYGENIC DISEASE IS MORE
MULTIPLE SMALLER RISK VARIANTS
COMING TOGETHER, PLAYING A ROLE.
WE CAN DO SOME INTERESTING
STATISTIC MODELING BY BASICALLY
HAVING A STATISTICAL TOOL TO SUM
UP THE POLYGENIC RISK, SO YOU
MAY HAVE MULTIPLE DIFFERENT
SMALL RISK VARIANTS, WHICH IS
UNLUCKY ENOUGH, AND IF YOU HAVE
A LOT, IT CAN REALLY AFFECT THE
WAY YOU PRESENT, AFFECT THE AGE
THAT YOU PRESENT, AFFECT THE
SEVERITY.
AND SO WE CAN USE THAT FOR
MULTIPLE DIFFERENT THINGS.
WE CAN USE POLYGENIC RISK SCORES
TO EXAMINE THE RELATIONSHIPS
BETWEEN COMPLEX TRAITS, WE CAN
SUBSTRATIFY PATIENTS BASED ON
HIGH POLYGENIC RISK VERSUS NO
POLYGENIC RI RISKS, AND WE CAN K
AT INTERESTING PHENOTYPE
CORRELATIONS.
SO NOW OUR COHORT, WE COULD
DEMONSTRATE TA TIS PARTICULARLY
THAT THERE'S A REAL GENETIC
OVERLAP BETWEEN LEWY BODY
DEMENTIA, ALZHEIMER'S DISEASE
AND PARKINSON'S DISEASE.
SO BY ESSENTIALLY APPLYING THE
POLYGENIC RISK SCORES THAT WE
HAVE DEVELOPED FOR PARKINSON'S
DISEASE AND ALZHEIMER'S DISEASE
TO OUR LEWY BODY DEMENTIA
POPULATION, WE CAN SEE THEY
ARE -- THEY HAVE A STATISTICALLY
HIGHER RISK AND IT REMAINS HIGH
EVEN WHEN WE REMOVE THE HIGH
RISK VARIANTS.
WE ALSO ARE SEEING ENRICHMENT OF
GENETIC DEFECTS IN CERTAIN
PATHWAYS THAT ARE ALWAYS COMING
UP IN NEURODEGENERATION AND THE
THING THAT'S REALLY EMERGING IS
PATHWAYS THAT ARE IMPORTANT FOR
PROTEIN DEGRADATION, FOR ENDO
LYSOSOMAL TRANSPORT.
SO AGAIN AND AGAIN, IT
HIGHLIGHTS PATHWAYS REALLY
RELEVANT FOR THERAPY DEVELOPMENT
ACROSS THE WHOLE GAMUT OF
NEURODEGENERATIVE DISEASES.
NOW I WANT TO SWITCH GEARS A
LITTLE BIT.
SO EVERYTHING THAT I HAVE TOLD
YOU SO FAR HAS REALLY BEEN
FOCUSED ON SMALL GENETIC
CHANGES, SINGLE LETTER CHANGES
IN THE GENOME.
BUT THERE ARE ACTUALLY A LOT OF
OTHER CHANGES THAT CAN HAPPEN IN
THE GENETIC CODE.
AND LARGER CHANGES ARE SO CALLED
STRUCTURAL VARIANTS WHERE YOU
HAVE EITHER AN ENTIRE ADDITIONAL
TRUNK OR SOMETHING IS MISSING OR
SOMETHING IS INVERTED, AND
INTERESTINGLY ACTUALLY, THESE
CHUNKS OR STRUCTURAL VARIANTS
ARE ACTUALLY AN IMPORTANT SOURCE
IN OUR EVOLUTION.
AND WE DON'T UNDERSTAND THEM
QUITE AS WELL, IT'S VERY
DIFFICULT TO STUDY THEM AND TO
MAP THEM SYSTEMATICALLY, BUT WE
HAVE GOOD REASON TO SUSPECT THAT
THEY COULD PLAY AN IMPORTANT
ROLE IN LEWY BODY DEMENTIA BASED
ON RARE FAMILIES WHERE WE HAVE
SEEN HAVING EXTRA COPIES FOR
EXAMPLE OF THE SCNA GENE, GBA
RECOMBINATION ARE RARE CAUSE OF
IT.
SO WE HAVE GENOME SEQUENCE DATA,
WE WERE ABLE TO USE MODERN
COMPUTATIONAL TOOLS TO
ESSENTIALLY PREDICT STRUCTURAL
VARIANTS ACROSS THE ENTIRE
GENOME, AND THEN INSTEAD OF
SINGLE KNEW CLEE T NUCLEOTIDE CD
STRUCTURAL TESTING AGAIN.
ONE OF THE VERY FIRST ONES IN
THE WORLD TO REALLY USE A GENOME
WIDE STRUCTURAL VARIANT
ASSOCIATION STUDY.
SO EVERY DOT ON THIS MAN TA TAN
MANHATTANPLOT IS ACTUALLY A STRL
VARIANT.
LO AND BEHOLD WHEN WE DID THIS
ANALYSIS, WE SAW ANOTHER RISK
GENE POP UP THAT WE DIDN'T SEE
USING THE SINGLE VARIANT
ANALYSIS, WHICH WAS A DELETION
POLYMORPHISM THAT IS ACTUALLY
QUITE PREVALENT IN THE LEWY BODY
DEMENTIA POPULATION.
IT HAS A SIGNIFICANT RISK.
ABOUT 1.4.
AND WE WERE ABLE TO REPLICATE
IT, VALIDATE IT USING LONG-READ
SEQUENCING.
IT'S PRESENT IN ABOUT 8% OF
CASES.
WE WERE IMMEDIATELY EXCITE TODAY
FIND THAT BECAUSE IT ACTUALLY IS
A GENE THAT HAS BEEN IMPLICATED
PREVIOUSLY IN ALZHEIMER'S
DISEASE, AND SO THIS IS A GWAS
STUDY THAT INDICATED THIS
PARTICULAR LOCUS BEFORE, IT
DIDN'T QUITE REACH SIGNIFICANCE
BUT IT REALLY WAS ONE OF THE
SUGGESTED LOCI.
AND THERE'S ALREADY BEEN SOME
WORK ON THIS PARTICULAR GENE.
IT'S A TWO PORT CHANNEL,
ENDOLYSOSOMAL CHANNEL,
INHIBITION COULD ACTUALLY
AMELIORATE PATHOLOGY, SO IT
REALLY HAS AN IMPACT SO IT'S AN
INTERESTING TARGET FOR LEWY BODY
DEMENTIA.
NOW THAT WE KNOW THAT
TPCN1 SEEMS TO BE PLAYING A ROLE
IN ALZHEIMER'S DISEASE AND LEWY
BODY DEMENTIA, WE DID A LITTLE
BIT MORE WORK SO WE BASICALLY
ZOOMED IN ON THE ASSOCIATION
SIGNALS THAT EXIST IN
ALZHEIMER'S DISEASE GWAS STUDIES
VERSUS LEWY BODY DEMENTIA GWAS
STUDIES AND LO AND BEHOLD, WE DO
SEE A VERY STRONG CORRELATION,
IT REALLY SEEMS TO BE THE SAME
RISK GENES THAT SEEMS TO BE
SHARED BETWEEN THOSE TWO
DEMENTIA SYNDROMES.
HOWEVER, WE DO NOT SEE SUCH A
RELATIONSHIP WITH PARKINSON'S
DISEASE, SO IT REALLY SEEMS TO
BE ONE THAT'S MORE ASSOCIATED
WITH ALZHEIMER'S AND LEWY BODY
DEMENTIA PATHOLOGIES.
ALL RIGHT.
SO ONE OF THE THEMES THAT ARE
CLEARLY EMERGING IS THIS TEAM
THAT YOU CAN HAVE A RISK GENE
AND IT CAN BE INVOLVED IN A
WHOLE HOST OF DIFFERENT
DISEASES, AND SO THE TECHNICAL
TERM FOR THAT IS GENETIC
PLEIOTROPY.
IT'S GOOD NEWS IN A WAY BECAUSE
IT INDICATES THERE IS SHARED
BIOLOGY IN THE BACKGROUND, AND
THAT BIOLOGY IS SOMETHING THAT
WE CAN WORK WITH IN OUR MODEL
SYSTEM AND IN OUR DRUG SCREENS.
AND SO THERE ARE MULTIPLE
EXAMPLES NOW IN LEWY BODY
DEMENTIA WHERE WE HAVE SEEN
THAT, BUT ALSO BEYOND THAT.
AND I JUST WANT TO HIGHLIGHT ONE
OTHER SUCCESS STORY ALONG THOSE
LINES WHICH IS WHERE WE HAVE
LOOKED AT MUTATIONS IN A KNOWN
NEURODEGENERATIVE DISEASE.
THE REASON FOR THAT WAS BECAUSE
MANY PATIENTS WITH MUTATIONS IN
THAT GENE ACTUALLY HAVE LEWY
BODY PATHOLOGY IN ADDITION TO
FRONTOTEMPORAL DEMENTIA
PATHOLOGY, THE TDP43 PATHOLOGY.
SO WE HAD HYPOTHESIZED MAYBE
THERE IS AN ACTUAL RELATIONSHIP.
LO AND BEHOLD ONCE WE LOOKED, WE
SAW NOTES OF KNOWN DISEASE
CAUSING MUTATIONS ENRICHED IN
OUR LEWY BODY DEMENTIA PATIENT
POPULATION, ALTHOUGH THEY ARE
RARE, THEY DO EXIST, AND WE DO
SEE GENUINE COPATHOLOGY, SO WE
SEE THE SINGLE -- PATHOLOGY WE
ASSOCIATE WITH LEWY BODY
DEMENTIA BUT WE ALSO SEE TD
TDP43 PATHOLOGY, WHERE IT'S BEEN
ORIGINALLY DESCRIBED.
CLINICALLY THESE CASES REALLY
CAN HAVE EITHER WAY, THEY CAN
PRESENT WITH MORE FRONTOTEMPORAL
DEMENTIA-LIKE PRESENTATIONS OR
AS IN OUR CASE WHAT REALLY LOOKS
LIKE CLASSICAL CLINICAL DEMENTIA
WITH LEWY BODIES.
WHAT THAT MEANS IS THAT IT'S
IMPORTANT TO RECOGNIZE THESE
CASES BECAUSE INCREASINGLY WE
CAN USE GENETIC INFORMATION IN
THE CLINICAL SETTING, WE CAN
IDENTIFY THESE PATIENTS, AND CAN
FUNNEL THEM INTO GENE THERAPY
TRIALS AND OTHER TARGETED
THERAPEUTIC INTERVENTIONS, SO
FOR THOSE CASES IT'S REALLY
IMPORTANT TO RECOGNIZE THEM.
AND ACTUALLY TARGETED CLINICAL
TRIALS THAT ARE ACTUALLY ONGOING
SO INTERESTING TO KNOW.
SO THAT REALLY BRINGS ME TO THE
LAST SECTION OF MY PRESENTATION,
WHICH IS, YOU KNOW, IT'S NICE
ACADEMIC EXERCISE THAT WE'RE
DOING HERE, BUT WHAT DOES IT
ACTUALLY MEAN FOR THE PATIENTS?
SO THERE ARE SOME VERY IMMEDIATE
IMPLICATIONS FOR THE CLINICAL
PRACTICE, SO ONE IS THAT WE
INCREASINGLY ACTUALLY OFFER
GENETIC COUNSELING, GENETIC
TESTING IN OUR DEMENTIA
POPULATION.
BUT THAT REALLY HAS CHANGED OVER
THE LAST 10 YEARS.
AND YOU KNOW, WE CAN OFFER THAT
NOT JUST TO PATIENTS WITH CLEAR
FAMILY HISTORY BUT ALSO
APPARENTLY SPORADIC CASES.
REASON WHY IT IS HELPFUL IS
BECAUSE IT CAN HELP US WITH
ESTABLISHING THE MOLECULAR
DIAGNOSIS WHEN WE'VE IDENTIFIED
MAINTAINING DISEASE, BUT IT CAN
ALSO REALLY REFINE OUR ABILITY
TO COUNSEL AND TO STUDY AND
FOLLOW THESE PATIENTS AND GET
THEM INTO THE RIGHT KIND OF
CLINICAL TRIALS THAT ARE
BECOMING MUCH, MUCH MORE PRECISE
AND MUCH, MUCH MORE FOCUSED ON
CERTAIN MOLECULAR SUBTYPES.
AND THERE'S GOOD REASON TO BE
HOPEFUL AND TO HAVE THE CLASS IS
HALF FULL KIND OF ATTITUDE.
SO GENOMICS HAS REALLY BEEN
REVOLUTIONIZING THE DRUG
DEVELOPMENT PI PIPELINE.
THERE'S BEEN MULTIPLE SUCCESS
STORIES.
INTERNAL MEDICINE AND
NEUROLOGISTS WE STILL HAVE TO
CATCH UP AS WE'RE MAPPING OUT
THE GENETIC ARCHITECTURE FOR
MANY OF THE DISEASES.
SO IN 2021, ABOUT A THIRD OF
APPROVED DRUGS HAVE HAD GENETIC
SUPPORT AND IT'S GOING UP
BECAUSE WE'RE STARTING TO HAVE A
REAL ANCHOR AS TO HOW WE MODEL
THE DISEASES AND HOW WE
UNDERSTAND DISEASES AND
ULTIMATELY HOW WE TARGET THE
DEEDS, AND THAT'S REALLY WHERE
WE'RE TRYING TO GO.
I'M GOING TO SHOW YOU ONE STUDY
WHERE WE HAVE IMPLICATED
INTERESTING DRUGS FOR LEWY BODY
DEMENTIA SPECIFICALLY, AND HOW
WE CAN LEVERAGE GENOMIC DATA TO
REALLY PROVIDE MOLECULAR
SUPPORT.
SO THIS IS A STUDY THAT ONE OF
MY PANDEMIC EXERCISES WITH
DR. RUTH PFEIFFER FROM NCI THAT
REALLY LOOKED AT THE U.S.
MEDICARE CLAIMS DATABASE, A
HEALTHCARE DATABASE FOR
INDIVIDUALS OF THE AGE OF 65 OR
ABOVE.
AND BASED ON THAT, WE WERE ABLE
TO QUERY WHICH ARE PATIENTS WHO
HAVE LEWY BODY DEMENTIA AND WHO
ARE NEUROLOGICALLY HEALTHY
CONTROLS, SO YOU CAN REALLY PULL
THEM OUT.
AND THEN WHAT WE DID WAS WE
LOOKED AT THOSE THAT HAD LEWY
BODY DEMENTIA AND REVIEWED WHAT
WAS THE DRUG PRESCRIPTION
PATTERN THREE YEARS BEFORE THEY
MANIFESTED WITH DISEASE.
AND WE WANT TO GO INTO THE
PRODROMAL PHASE OF THE DISEASE
WHERE WE REALLY WANT TO
POTENTIALLY HELP THE PATIENT, WE
WANT TO KNOW WHAT'S POTENTIALLY
PROTECTED.
AND SO WHAT WE WERE QUITE
ASTONISHED TO FIND WAS THAT ANY
OF THE CARDIOVASCULAR DISEASE
MANAGEMENT DRUG CLASSES WAS
COMING UP AS PROTECTIVE AND THAT
REALLY HIGHLIGHTS THE OVERALL
THEME OF OUR TALK TODAY, THE
VASCULAR RISK FACTOR IS REALLY
IMPORTANT IN NEURODEGENERATION,
SO WE NEED TO PAY ATTENTION TO
IT.
BUT THAT WAS ONLY THE
EPIDEMIOLOGICAL PART OF THE
STUDY.
SO THEN ONCE WE SAW THAT, WE HAD
PROVE SEISHYPOTHESIZED -- BETWEN
CARDIOVASCULAR DISEASES AND LEWY
BODY DEMENTIA, WE KNOW THEIR
GENETIC ARCHITECTURE, THE RISK
SCORE FOR HYPERTENSION, WE CAN
ACTUALLY LOOK AT GENETIC
CORRELATIONS.
WHEN WE DID THAT, LO AND BEHOLD
WE FOUND SIGNIFICANT GENETIC
CORRELATIONS BETWEEN CARD JOE
VASCULAR DISEASE GENETIC
ARCHITECTURE AND LEWY BODY
DEMENTIA.
AND IN DOING SO CALLED
CONDITIONAL ANALYSIS, WE COULD
REALLY MODEL THAT IF YOU HAVE
ONE OF THOSE CARDIOVASCULAR
DISEASE RISK FACTORS, YOU REALLY
HAVE A HIGHER RISK OF LEWY BODY
DEMENTIA, AND THAT REALLY
SUGGESTS WE NEED TO BE PAYING
CLOSE ATTENTION TO THESE RISK
FACTORS IN THE MANAGEMENT OF OUR
PATIENTS AS THEY COULD BE REALLY
DISEASE MODIFYING.
I'M CERTAINLY NOT THE FIRST ONE
TO IMPLICATE THAT.
THERE'S REALLY AN EMERGING BODY
OF LITERATURE THAT SUGGESTS THAT
THESE VASCULAR RISK FACTORS ARE
REALLY DRIVING NEURODEGENERATION
ON A BIG SCALE, SO ACROSS THE
DEGENERATIVE DISEASES, DIABETES
MELLITUS INCREASES YOUR RISK FOR
NEURODEGENERATION AND IT SEGUES
QUITE NICELY INTO REBECCA'S
TALK, WHERE WE CAN REALLY REVIEW
HOW EXACTLY THAT INTERPLAY MAY
BE TAKING PLACE.
AND THE REAL CAUSAL
RELATIONSHIPS, THESE ARE
MODIFIABLE RISK FACTORS SO WE
CAN DO SOMETHING ABOUT THAT.
WE DON'T ALWAYS HAVE TO WAIT FOR
GENE THERAPY, ADDRESSING
VASCULAR RISK FACTORS IN
NEURODEGENERATION IS REALLY
IMPORTANT.
SO WHERE THE OVERALL FIELD IS
GOING WITH THE GENOMIC
INFORMATION IS THAT, YES, WE'RE
LEARNING MORE ABOUT THE
UNDERLYING MOLECULAR MECHANISM
THAT ARE INVOLVED IN UNDERLYING
MOLECULAR PATHWAYS AND WE CAN
PINPOINT CERTAIN INTEREST IN
THOSE THAT ARE AFFECTED NOT JUST
IN OUR DISEASE OF INTEREST BUT
ACROSS THE BROADER SPECTRUM THAT
HELPS US PR PRIORITIZE WHICH DRS
TO PUT INTO THE PIPELINE, WHICH
DRUGS WE SHOULD ACTUALLY BRING
FORTH FOR CLINICAL TRIALS.
ULTIMATELY REALLY THE GENETICS
IS THE DRIVING ENGINE BEHIND
WHAT WE KNOW AS POSITION --
WHERE WE TRY TO REALLY BRING IN
THE RIGHT KIND OF TREATMENT FOR
THE RIGHT PATIENT, THE RIGHT
POINT OF TIME, AND THAT'S REALLY
WHAT THE GOAL IS.
SO THE KEY MESSAGES IN THE FIRST
HALF OF THE TALK WAS I WANTED TO
REALLY HIGHLIGHT THAT THERE ARE
RAPID ADVANCES IN OUR
UNDERSTANDING OF SO CALLED
NON-ALZHEIMER'S DEMENTIAS AND
REAL INTRICATE RELATIONSHIPS
BETWEEN VASCULAR RISK AND
NEURODEGENERATION.
WE'RE INCREASING USER MOLECULAR
INSIGHTS TO DEVELOP NEW
THERAPIES AND HOPEFULLY BRING A
CURE FOR THE DEMENTIA EPIDEMIC
THAT WE'RE DEALING WITH RIGHT
NOW.
SO WITH THAT, I WANT TO
HIGHLIGHT, THIS IS ALL TEAM
SCIENCE THAT I'M SHOWING YOU
HERE, SO NONE OF THAT IS MY
WORK, IT IS ALL OUR WORK AND WE
HAVE A FABULOUS NEUROSCIENCE
COMMUNITY HERE AND WE HAVE LODZ
OF GREAT SUPPORTERS AND
COLLABORATORS, SO I'M VERY
GRATEFUL ALSO TO UR A PATIENT'S
AND FAMILIES FOR WORKING WITH US
AND NEVER GIVING UP HOPE.
SO WITH THAT, I'M GOING TO STOP
HERE AND HAND OVER THE PODIUM TO
REBECCA FOR HER TALK.
>> WONDERFUL.
THANK YOU SO MUCH, SONJA, FOR AN
ABSOLUTELY WONDERFUL TALK.
THANK YOU FOR HAVING ME.
I'M SO SORRY THAT I'M NOT THERE
IN PERSON.
TO INTERACT WITH EVERYONE.
ABOUT I'M REALLY LOOKING FORWARD
TO CONTINUED DISCUSSION AT THE
END OF MY TALK.
SO AS SONJA BEAUTIFULLY OUTLI
OUTLINED, I'M GOING TO TALK
ABOUT THE VASCULAR CONTRIBUTIONS
TO DEMENTIA BROADLY AND TO
NEURODEGENERATION.
AND I'M REALLY -- THANK YOU,
SONJA, FOR GOING OVER SOME
REALLY IMPORTANT EVIDENCE BOTH
FROM YOUR OWN WORK BUT ALSO IN
THE CONTEXT OF HOW WE THINK
ABOUT DEMENTIA MORE BROADLY.
HERE ARE MY OWN DISCLOSURES
FUNDED BY THE INTRAMURAL
RESEARCH PROGRAM AT NINDS.
SO YOU'VE HEARD THIS MESSAGE
ALREADY AND I DON'T WANT TO
DWELL ON IT TOO MUCH BUT REALLY,
WE KNOW THAT AS THE POPULATION
AGES, THE EPIDEMIC OF DEMENTIA
BROADLY IS A GROWING THREAT IN
THE COMING DECADES.
POTASSBOTH IN HIGH-INCOME COUNTS
AND EVEN MORE SO IN ID EL INCOME
COUNTRIES AS YOU CAN SEE IN THIS
GRAPHIC.
AS YOU'VE HEARD, ALZHEIMER'S
DISEASE IS THE LEADING CAUSE OF
DEMENTIA.
ALTHOUGH THERE ARE SOME
TREATMENTS AVAILABLE AND OTHERS
IN THE WORKS, GENERALLY EFFECT
SIZES HAVE BEEN MODEST OR DRUGS
HAVE BEEN INEFFECTIVE WHERE IT'S
NOT CLEAR THAT THEY MODIFY THE
PATH OF DISEASE IN GENERAL.
SO THIS IS WHY THINKING WITH
VASCULAR RISK AND VASCULAR
CONTRIBUTIONS IS REALLY
APPEALING.
I WANT TO TELL YOU A LITTLE BIT
ABOUT VASCULAR DEMENTIA.
SO IN THEORY, THE IDEA OF
VASCULAR DEMENTIA, HI WISCONSIN
HAS ALSO BEEN CALLED
MULTI-INFARCT DEMENTIA,
SOMETIMES BINSWANGERS TO REFER
TO SUBCORTICAL VASCULAR
DEMENTIA, OR CADASIL, THESE ARE
ALL DIFFERENT TYPES OF VASCULAR
DEMENTIA.
IN GENERAL, THE CLASSICALLY
DEFINED IS RAPID ONSET, STEP
WISE PROGRESSION OF SYMPTOMS,
SOMETIMES AFTER A STROKE BUT
OFTEN NOT.
ANTITHE NINDS-AIREN CRITERIA
ESTABLISHED IN 1993 REQUIRE THE
PRESENCE OF THOSE COMPONENTS, SO
SOME FORM OF SCREEN ROW VASCULAR
DISEASE, WHETHER A STROKE OR
FINDINGS ON NEUROIMAGING,
DEMENTIA, AND THEN RELATIONSHIP
BETWEEN THE TWO THAT APPEARS TO
LINK THEM.
SO THE DIAGNOSIS IN GENERAL
REQUIRES BOTH THE COGNITIVE
DISORDER AND THEN EITHER STROKE
OR EVIDENCE OF INFARCT OR
STROKE-LIKE FINDINGS ON IMAGING.
HERE'S AN EXAMPLE, THIS IS AN
MRI WITH A LARGE STROKE, HERE'S
EVIDENCE OF BRIGHT MATTER
HYPERINTENSITIES, WHICH ARE
OFTEN SEEN IN PEOPLE WITH
LONG-STANDING HYPERTENSION.
WE'LL TALK A LITTLE BIT ABOUT
THAT LATER.
YOU HEARD A BIT ABOUT THE
DOMAINS, THE COGNITIVE DOMAINS
OF THE MOST COMMONLY AFFECTED,
PEOPLE WITH ALZHEIMER'S DISEASE
AS WELL AS OTHER NON-AD
DEMENTIAS FOR VASCULAR DEMENTIA,
THE CLASSIC SET OF DOMAINS THAT
ARE AFFECTED ARE EXECUTIVE
FUNCTION AND ATTENTION.
MEMORY MAY NOT BE AS AFFECTED
WHICH MEANS SOMETIMES THIS IS
DIAGNOSED AT A LATER STAGE IN
THE DISEASE.
AND CLINICALLY, WE THINK ABOUT
VASCULAR DEMENTIA AS THE SECOND
LEADING CAUSE OF DEMENTIA,
ACCOUNTING FOR THAT 20% OF DMEP
DEMENTIA CASES AND THE ESTIMATES
ARE CERTAINLY A LOT LOWER FOR
WHAT WE SEE FOR ALZHEIMER'S
DISEASE.
THE PROBLEM IS, PURE VASCULAR
DEMENTIA REALLY FITTING THESE
CRITERIA AND BY THESE
DEFINITIONS IS RELATIVELY RARE.
THIS IS FOR THE SAME REASONS
THAT SONJA JUST OUTLINED THAT
I'M GOING TO GET INTO IN A LOT
MORE DETAIL.
SO IN GENERAL WHEN WE THINK
ABOUT VASCULAR DEMENTIA, THERE'S
BEEN A SHIFT TO NOT THINK ABOUT
THIS PURE ENTITY THAT OCCURS
AFTER A STROKE OR IN EVIDENCE OF
THESE IMAGING MARKERS AND HAS
THE STEP WISE PROGRESSION BUT
WHAT WE CALL VASCULAR
CONTRIBUTIONS TO COGNITIVE
IMPAIRMENT AND DEMENTIA.
SO HERE'S A NICE BEAUTIFUL
GRAPHIC FROM ROB CORRIVEAU HAS
PUBLISHED AND USES A LOT WHEN I
DISCUSSES THIS CONCEPT OF A
VCID, WHICH ALLOWS US TO HAVE A
BROADER SET OF TERMS THAT REFER
TO THE MANY DIFFERENT WAYS THAT
VASCULAR RISK AND VASCULAR
HEALTH CAN AFFECT COGNITIVE
COMEN SLA AND BRAIN HEALTH IN
GENERAL.
AS YOU CAN SEE THERE'S A LONG
LIST OF POSSIBLE WAYS AND
POSSIBLE SUBSETS OF VASCULAR
CONTRIBUTIONS TO DEMENTIA,
RANGING FROM STROKE ITSELF TO
MICRO INFARCTS AND SMALL VESSEL
DISEASE AND OTHER CHANGES IN
BETWEEN.
INCLUDING THINGS LIKE CEREBRAL
AMYLOID ANGIOPATHY, FORMING
PLAQUES AND PAREN MA IN
ALZHEIMER'S DISEASE, IN THIS
CASE YOU GET FILLED UP IN THE
BLOOD VESSEL WALL, THAT'S
ANOTHER FORM OF VASCULAR
CONTRIBUTIONS TO DEMENTIA.
HERE'S SOME EXAMPLES OF WAYS IN
WHICH VASCULAR DISEASE AND
ADVERSE VASCULAR HEALTH CAN
AFFECT COGNITIVE HEALTH AND
DEMENTIA.
THIS IS A WORKSHOP WHERE WE
PUBLISHED THE FINDINGS AFTER A
GROUP OF EXPERT GOT TOGETHER AND
THOUGHT ABOUT ALL OF THE
POTENTIAL MECHANISMS BY WHICH
VASCULAR RISK MIGHT AFFECT THE
BRAIN AND NEURONAL HEALTH, AND
HEALTH OF THE NEUROVASCULAR
UNIT.
AND CERTAINLY THERE'S FURTHER
WORK ON THESE MECHANISMS, I'LL
TALK A LITTLE WITH THEM SHORTLY
BUT I MOSTLY WANT TO FOCUS ON
THE EPIDEMIOLOGY OF WHAT WE KNOW
ABOUT VASCULAR CONTRIBUTIONS TO
DEMENTIA.
OKAY, I TOLD YOU I WOULD SHARE
ANOTHER PIE CHART.
HERE IS ANOTHER PIE CHART, AND
THESE ARE DATA FROM THE SAME
STUDY BUT BY JULIE SCHNEIDER
THAT SONJA PRESENTED EARLIER.
THIS HAS SHOWN YOU AGAIN, AMONG
PEOPLE WITH A CLINICAL DIAGNOSIS
PREMORTEM OF PROBABLE AD, OR
MILD COGNITIVE IMPAIRMENT OR
MCI, A PRECURSOR OFTEN TO.
A D, BUT A LESS THAN HALF AND
HER GRAPH IS MORE UPDATED
INCLUDES NEWER PATHOLOGIES SUCH
AT LATE THAT WE DIDN'T KNOW
ABOUT IN SOME OF THESE EARLIER
STUDIES, THAT PURE AD ITSELF,
EVEN IN SOMEONE WHO'S FELT
CLINICALLY TO HAVE PURE AD IS
RELATIVELY UNCOMMON, THAT IS NOT
ACCOUNTING FOR MOST CASES.
YOU CAN SEE HERE, THIS IS THESE
DIFFERENT PIE PIECES THAT ARE
ACCOUNTING FOR I BEING INFARCT,
LB BEING LUO B LEWY BODY, MANY E
FOUND TO HAVE THESE OVERLAPPING
PATHOLOGIES.
IN GENERAL, PATIENTS AT A
CERTAIN COGNITIVE LEVEL BEFORE
DEATH, THOSE WHO HAVE MORE
VASCULAR CHANGES IN THE BRAIN
HAVE FEWER ALZHEIMER'S DISEASE
CHANGES TO GET TO THAT
EQUIVALENT COGNITIVE LEVEL AND
IN GENERAL, WE JUST VERY
FREQUENTLY SEE THESE VASCULAR
CHANGES IN THE BRAIN OF PEOPLE
WHO DIE OF ALZHEIMER'S DISEASE.
AND OF NEURODEGENERATIVE
DISEASES IN GENERAL.
SO REALLY THINKING ABOUT HOW
THESE PATHOLOGIES OVERLAP IS
IMPORTANT.
VCID CAN TAKE A LOT OF DIFFERENT
FORMS AND VASCULAR DEMENTIA
ALTHOUGH IN A PURE FORM IS
RELATIVELY RARE, THIS IDEA OF
VCID MORE BROADLY IS NOT SO RARE
BUT IT'S GOING TO LOOK DIFFERENT
IN DIFFERENT PEOPLE.
SO HERE'S ALITTLE MORE DATA
WHERE I JUST SHARED SOME OF THE
INITIAL DATA.
WE HAVE 2,000 INDIVIDUALS WITH
POSTMORTEM EXAMS.
OVER HALF HAD SOME TYPE OF MIXED
THAT POLG,THAT POLG, AND A FIFTE
THOUGHT TO HAVE
NEURODEGENERATION HAD PURE
VASCULAR PATHOLOGY WITHOUT
NEURODEGENERATION, ANOTHER
QUARTER HAD NEURODEGENERATION
WITHOUT VASCULAR CHANGES AND WE
VERY FREQUENTLY SAW INFARCTS AS
WELL AS MICRO INFARCTS AS WELL.
THIS WAS INDEPENDENT OF CLINICAL
HISTORY OF STROKE.
SO THERE'S A LOT OF DIFFERENT
FORMS THIS CAN TAKE DID YOU WE
KNOW IN GENERAL THE MORE
VASCULAR DISEASE YOU HAVE, THE
WORSE YOUR COGNITION IS, AND
THIS IS SOMETHING THAT THEY SAW
CONSISTENTLY.
I WANT TO TALK A LITTLE BIT MORE
ABOUT ONE POTENTIAL FORM OF VCID
BEFORE I TALK ABOUT THE EVIDENCE
LINKING VASCULAR RISK WITH
DEMENTIA BECAUSE WE'RE GOING TO
TALK A LITTLE ABOUT NEUROIMAGING
AAS A WAY TO LINK THEM WITH
DEMENTIA AND ALZHEIMER'S
DISEASE.
SO CEREBRAL SMALL VESSEL DISEASE
IS ONE FORM OF VCID AND OFTEN A
COMMON ONE THAT WE THINK OF WHEN
WE'RE TALKING ABOUT VASCULAR
CONTRIBUTIONS TO DEMENTIA AND
COGNITIVE IMPAIRMENT.
THE STRIVE CONSORTIUM PUBLISHED
A SET OF CRITERIA BY WHICH WE
SHOULD BE THINKING ABOUT SMALL
VESSEL DISEASE BUT IN GENERAL,
THESE FINDINGS ARE SILENT
INFARCTS AND LARGE PERIVASCULAR
SPACES, THOSE WHITE MATTER
HYPERINTENSITIES SHOWN ON
EARLIER MRI SCAN, CEREBRAL
MICROBLEEDS, NEURODEGENERATIVE
PRPROCESSES.
THIS WAS VERY INFORMATIVE AND
USEFUL IN HELPING MAKE SURE
WE'RE SPEAKING THE SAME LANGUAGE
IN THE FIELD AND REALLY THINK
ABOUT ARE THESE POTENTIAL
BIOMARKERS IN WHAT'S HAPPENING
IN VCID CASES.
SO I SAID I'D SHARE A LITTLE
MORE ABOUT MECHANISMS LINKING
VASCULAR RISK WITH AD AND SONJA
DID A BEAUTIFUL JOB TALKING
ABOUT GENETIC OVERLAPS AND WHY A
LOT OF THESE CONDITIONS --
GENETICS MAY BE AN INCREDIBLY
VALUABLE WAY TO UNDERSTAND HOW
MECHANISMS MAY TIE THESE
DIFFERENT PATHOLOGIES TOGETHER,
BUT THERE'S ALSO GREAT EVIDENCE
LOOKING PURELY AT VASCULAR RISK
AND ALZHEIMER'S DISEASE
SPECIFICALLY, PARTICULARLY FOR
HYPERTENSION, WHICH IS A VERY
IMPORTANT RISK FACTOR THAT WE'LL
TALK ABOUT SHORTLY.
SO HERE'S A SUMMARY GRAPH AND A
PAPER FROM SEVERAL YEARS AGO BUT
THERE'S A FEW DIFFERENT
MECHANISMS THAT HAVE BEEN
HYPOTHESIZED.
CERTAINLY WE KNOW VASCULAR RISK
FACTORS OVER TIME CAN ALTER
CEREBRAL BLOOD FLOW WHICH CAN
LEAD TO REDUCTION OF WHITE
MATTER OF THE BRAIN.
WE CERTAINLY KNOW THE BLOOD
BRAIN BARRIER MAY NOT FUNCTION
AS WELL AND THE NEUROVASCULAR
UNIT ITSELF MAY BE IMPAIRED IN
THE PRESENCE OF VA VASCULAR RISK
FACTORS WHICH IN TURN CAN LEAD
TO AMYLOID PRODUCTION, IMPORTANT
PLAYER IN THE DEVELOPMENT OF
ALZHEIMER'S DISEASE, AND THAT IN
TURN CAN LEAD TO WORSE VASCULAR
HEALTH AND CEREBRAL BLOOD FLOW.
THE LIMB LYMPHATIC SIM TEM WHIS
FELT TO DRAIN TOXINS INCLUDING
POTENTIALLY TOXIC PROTEINS LIKE
AMYLOID BETA, IN THE PRESENCE OF
VASCULAR DISEASE, THE LYMPHATIC
SYSTEM MAY NOT FUNCTION AS WELL,
SO THIS IS ONE OTHER MECHANISM
BY WHICH VASCULAR DISEASE,
CHRONIC CONDITIONS LIKE
HYPERTENSION, CAN LEAD TO
ALZHEIMER'S MORE BROADLY.
ONE OTHER REALLY IMPORTANT AREA
IN MY OPINION AS TO WHY WE NEED
TO THINK ABOUT VASCULAR HEALTH,
THESE ARE RISK FACTORS WE KNOW
HOW TO TREAT, THEY'RE A PRO
TENSIONALLY MODIFIABLE WAY TO
ALTER THE RISK OF ALZHEIMER'S
DISEASE AND THAT'S REALLY WHAT
I'M GOING TO TALK ABOUT MORE
DETAIL BUT I ALSO WANT TO TALK
ABOUT IN GENERAL ALZHEIMER'S
DISEASE HAS THIS VERY LONG
PRE-CLINICAL PERIOD.
SO YOU CAN SEE HERE IN WHAT'S
CALLED THE JACK CURVE THAT CLIFF
JACK PUBLISHED ON, THAT IN
GENERAL, COGNITION STARTS TO BE
AFFECTED RELATIVELY LATE IN THE
COURSE OF ALZHEIMER'S DISEASE.
SO THIS IS SHOWING YOU THE
COGNITIVE CHANGES, BUT ALL
BIOMARKER CHANGES THAT OCCUR IN
PROBABLY THE DECADES PRECEDING
COGNITIVE CHANGE.
SO PART OF THE REASON THAT MANY
ALZHEIMER'S TREATMENTS TO DATE
HAVE NOT BEEN EFFECTIVE, NOT AS
EFFECTIVE AS THEY MIGHT, IS
BECAUSE THEY MIGHT BE STARTING
WHEN PEOPLE ARE TOO FAR ALONG
THAT PROCESS.
SO IF THE DISEASE HAS ALREADY
STARTED, LEADING TO ALL THESE
ALTERATIONS IN VARIOUS
BIOMARKERS AND ALTERATIONS IN
AMYLOID AND TAU, IT MAY BE
REALLY TOO LATE TO CHANGE THE
COURSE OF THE DISEASE.
VASCULAR RISK IS ESPECIALLY
APPEALING BECAUSE INCREASING
EVIDENCE SUGGESTS THAT VASCULAR
RISK FACTORS ARE MOST STRONGLY
ASSOCIATED WITH DEMENTIA AND
POSSIBLY ALZHEIMER'S
SPECIFICALLY.
IF YOU LOOK AT THEM FROM MID
LIFE OR PROBABLY EVEN EARLIER,
ALTHOUGH THERE'S NOT AT MANY
STUDIES LOOKING EARLIER IN LIFE.
IN OTHER WORDS, VASCULAR HEALTH
AT A YOUNGER AGE APPEARS TO BE
MOST ASSOCIATED WITH YOUR BRAIN
HEALTH WHEN YOU'RE OLDER, AND
IT'S BEEN HYPOTHESIZED IN THIS
PARTICULAR MODIFICATION JACK
CURVE THAT VASCULAR
DYSREGULATION, I'M SURE YOU
CAN'T SEE ALL THESE SEPARATE
LINES BUT TAKE MY WORD THAT THIS
FIRST LINE HERE, THIS BROWNISH
LINE IS VASCULAR DYSREGULATION.
IT'S BEEN HIGH POT SIZED THAT
THAT MIGHT BE THE FIRST
CONDITION THAT OCCURS LEADING TO
OTHER PROTEIN ALTERATIONS AND
ULTIMATELY COGNITIVE CHANGE.
SO HAVING A MODIFIABLE RISK
FACTOR IS INCREDIBLY APPEALING.
HAVING ONE THAT YOU CAN
POTENTIALLY ALTER THE COURSE OF
DISEASE OR AT LEAST ALTER THE
COURSE OF THE PHENOTYPE OF THE
DISEASE AT AN EARLY ENOUGH STAGE
IS ESPECIALLY APPEALING.
SO I'M GOING TO SHARE SOME DATA
THAT I'VE BEEN A PART OF LOOKING
AT THE EPIDEMIOLOGIC EVIDENCE
LINKING VASCULAR RISK TO
COGNITIVE DECLINE IN DEMENTIA.
I JUST WANT TO SORT OF EXPAND
UPON THAT LAST POINT THAT I MA
MADE.
WE KNOW THAT VASCULAR RISK
FACTORS ARE MORE COMMON IN
INDIVIDUALS WITH DEMENTIA AND
ALZHEIMER'S DISEASE.
WHAT WE DON'T KNOW AND WHAT I
REALLY HAVE BEEN TRYING TO
UNDERSTAND AS MUCH AS IS
POSSIBLE IN THE OBSERVATIONAL
STUDIES IS WHETHER IT'S SIMPLY A
MATTER OF VASCULAR RISK IS VERY
COMMON, NEURO DEGENERATION SUCH
AS WE SEE IN ALZHEIMER'S DISEASE
IS VERY COMMON AND PEOPLE WHO
HAVE BOTH MAY BE MORE LIKELY TO
PASS A THRESHOLD OF COGNITIVE
PERFORMANCE WHERE THEY LOOK LIKE
THEY HAVE DEMENTIA AND ARE
CLINICALLY DIAGNOSED WITH
DEMENTIA, SO IS IT SIMPLY TWO
DIFFERENT PROCESSES THAT IN
COMBINATION MAKES SOMEONE MORE
LIKELY TO BE DIAGNOSED WITH
DEMENTIA OR IS THERE SOME DIRECT
MECHANISTIC LINK, AND SIMILARLY,
DOES IT ALTER THE PATHOGENESIS
OF THESE OTHER NON-AD DEMENTIAS
SUCH AS WHAT SONJA TALKED ABOUT.
SO TO TRY TO UNDERSTAND A LITTLE
BIT ABOUT THAT, WE CONDUCTED
SEVERAL STUDIES THAT I'M GOING
TO SHARE WITH YOU FROM THE ARIC
COHORT, NEARLY 16,000
INDIVIDUALS FROM FOUR U.S.
COMMUNITIES AS YOU CAN SEE HERE.
THEY WERE RECRUITED STARTING IN
MIDDLE AGE, 45 TO 64 IN THE LATE
1980s.
THEY'VE BEEN FOLLOWED NOW FOR
SEVERAL DECADES, ABOUT 35 YEARS
NOW.
THIS GRAPHIC STOPS AT VISIT
7 BUT WE'RE ACTUALLY JUST
STARTED YESTERDAY, I BELIEVE,
VISIT 11, WHICH WAS REALLY
EXCITING.
I'M MOSTLY SHARING DATA FROM
VISIT 7, BUT WE'RE CONTINUING TO
SEE PEOPLE.
BUT I WANT TO EMPHASIZE A FEW
THINGS.
FIRST OF ALL, THE AGE RANGE OF
THE COHORT, SO MIDDLE AGED WHEN
WE FIRST SAW THEM, NOW THEY'RE
80 TO 100.
AND CERTAINLY THE RATES OF
DEMENTIA ARE GOING UP AS
EXPECTED.
SIMILARLY ATTRITION DUE TO DEATH
AND OTHER DISEASES HAS GONE UP
AS WELL.
THEY WERE A POPULATION-BASED
COHORT SO NOT RECRUITED ON THE
BASIS OF HAVING EXISTENCE
VASCULAR OR OTHER DISEASE.
THEY'VE BEEN FOLLOWED FOR
COGNITIVE PERFORMANCE STARTING
AT AN EARLY VISIT REPEATED OVER
TIME.
AT THE FIFTH ARIC VISIT, WE
EXPANDED THE NEUROCOGNITIVE
BATTERY INCLUDED -- SO WE HAVE
EXPERT ADJUDICATION OF MILD
COGNITIVE IMPAIRMENT OF DEMENTIA
AND SUBSEQUENT VISITS INCLUDING
THE ONGOING ONES.
BRAIN MRI WAS ON A SUBSET OF
INDIVIDUALS AND THEN FLORBETAPIR
PET THAT BINDS TO AMYLOID IN THE
BRAIN WAS PERFORMED IN 346
PEOPLE FROM THREE OF THESE SITES
WHO WHO DID NOT HAVE DEMENTIA.
SO I'M GOING TO TALK A BIT ABOUT
SOME OF THESE DATA IN THE
CONTEXT OF THE COGNITIVE
RESULTS.
I'M GOING TO SHARE SOME DATA ON
COGNITIVE CHANGE AS WELL AS
INCIDENT DEMENTIA, SO WE HAVE
DEMENTIA CASES CLASSIFIED
BECAUSE WE SAW THEM IN DETAIL,
WE DID -- TALKED TO THEIR FAMILY
MEMBERS AND THE EXPERT
COMMUNITY -- WE HAVE PEOPLE THAT
WERE NOT ABLE TO COME IN, PHONE
INTERVIEWS WITH FAMILY MEMBERS
FOR PEOPLE WHO WERE DECEASED,
AND THEN FINALLY USE SOME
HOSPITALIZATION CODES TO MAKE
SURE WE HAD AS COMPLETE A SET OF
DATA ON DEMENTIA INCIDENTS AND
WE HAD ONGOING SURVEILLANCE IN
THE COHORT AS WELL.
THE LAST SORT OF PATHOLOGIC
POINT I WANT TO MAKE IS WHEN I
SHARE RESULTS WITH YOU, WE
CONSIDER ADRITION AND DROPOUT AS
REALLY IMPORTANT IN THINKING
ABOUT ASSOCIATIONS TBEEN BETWEEN
VASCULAR RISK AND DEMENTIA AND
COGNITIVE CHANGE.
THE REASON WHY IS PEOPLE WHO
HAVE A GREAT DEAL OF VASCULAR
RISK ESPECIALLY IN MIDDLE AGE
ARE THOSE WHO ARE LEAST LIKELY
TO MAKE TO A LATER VISIT DECADES
LATER TO ASSESS THEIR COGNITION.
SIMILARLY PEOPLE -- ARE THE
LEAST LIKELY AND COME IN FOR A
VISIT ASSESSING OF THEIR OWN
COGNITIVE FUNCTION.
SO IF WE IGNORE THOSE PEOPLE
THAT ARE LEAST LIKELY TO BE
FOLLOWED FOR THAT LONG PERIOD OF
TIME, VASCULAR DISEASE WHEN THEY
WERE YOUNGER, WE'LL HAVE AN
UNDERESTIMATION OF THE
ASSOCIATIONS IF WE'RE NOT SEEING
THE MOST AT-RISK PEOPLE.
SO STATISTICALLY, THERE'S WAYS
WE CAN UPWEIGHT THE PEOPLE WE
THINK ARE LEAST LIKELY TO MAKE
TO SUBSEQUENT VISITS.
SO I'LL SHOW YOU ONE EXAMPLE AS
TO HOW THAT ALTERS OUR RESULTS
AND IT'S IMPORTANT TO THINK
ABOUT IN ANY LONGITUDINAL STUDY
OF THIS TYPE.
SO HERE'S SOME OF OUR EVIDENCE.
ANDREA SCHNEIDER HERE AND -- DID
THE ANALYSES, SONJA ALREADY
MENTIONED THAT THERE'S BEEN A
GROWING BODY OF LITERATURE
LINKING THESE RISK FACTORS WITH
COGNITIVE CHANGE AND I WANT TO
EMPHASIZE HERE THAT THIS IS
REALLY OUR WAY OF LOOKING AT
THESE RISK FACTORS BUT ALSO
LOOKING IN PARTICULAR AT THE
IMPORTANCE OF MID LIFE FOR
REASONS I MENTIONED EARLIER.
IT'S A MODIFIABLE WINDOW, WE
THINK IT'S PROBABLY AN IMPORTANT
WINDOW FOR RELATIONSHIP TO LATE
LIFE BRAIN HEALTH, AND WE HAVE
FURTHER SUPPORT THESE
RELATIONSHIPS ARE QUITE A BIT
STRONGER WHEN YOU LOOK AT SOME
OF THE RISK FACTORS.
SO HYPERTHE HYPERTENSION HERE, D
BE CONSIDERED STAGE TWO
HYPERTENSION NOW, WAS -- IN MID
LIFE WAS ASSOCIATED WITH STEEPER
COGNITIVE DECLINE OVER THE NEXT
20 YEARS INDEPENDENT OF OTHER
RISK FACTORS AND DEMOGRAPHICS.
BUT LATE LIFE HYPERTENSION WAS
NOT ASSOCIATED WITH PRECEDING
YEARS, ABOUT 20 YEARS WORTH OF
COGNITIVE CHANGE.
YOU CAN JUST SEE HERE SORT OF
CONTINUOUS BLOOD PRESSURE
MEASUREMENTS AND STEEPER AMOUNTS
OF COGNITIVE DECLINE.
ANDREA LOOKED AT HEMOGLOBIN A1C
LEVELS, THIS IS YOUR X AXIS,
AMONG NON-DIABETICS, AND FOUND
WE HAVE STEEPER COGNITIVE
DECLINE, SO THIS IS MORE CHANGE
OVER 20 YEARS BEYOND WHAT'S
EXPECTED WITH AGE.
STEEPER COGNITIVE DECLINE OVER
20 YEARS WITH INCREASING
HEMOGLOBIN A1C EVEN IN THE
NON-DIABETIC RANGE.
ESTIMATES SHOW WHAT HAPPENS WHEN
YOU ACCOUNT FOR THAT ADRITION
THAT I MENTIONED.
SO HERE'S ON THE FAR RIGHT HERE,
THE HIGHER UP DOT SHOWS WHAT
HAPPENS IF YOU DON'T ACCOUNT FOR
ATTRITION AND YOU JUST MEASURE
ASSOCIATIONS IN THOSE PEOPLE WHO
DID HAVE FOLLOW-UP OVER TIME.
AND WHEN YOU ACCOUNT FOR THAT
ADRITATTRITION AND UPWEIGHT THOE
PEOPLE YOU'RE LEAST LIKELY TO
STAY IN THE STUDY BECAUSE OF
THEIR POORLY CONTROLLED DIABETES
IN LATE LIFE, YOU SEE GREATER
AMOUNTS OF COGNITIVE DECLINE
EXPECTED.
LIPIDS, WE SEE SOME RELATIONSHIP
BUT IT'S LESS STRONG AND
HYPERTENSION AND DIABETES.
HERE YOU CAN SEE HERE THE TOTAL
CHOLESTEROL LEVELS AS THEY WERE
HIGHER IN MID LIFE, AGAIN,
ASSOCIATED WITH STEEPER
COGNITIVE DECLINE OVER 20 YEARS.
THE ESTIMATE IS NOT AS LARGE AS
WE SEE FROM HYPERTENSION, WHICH
IS HERE FOR REFERENCE.
CERTAINLY NOT AS HIGH AS WHAT WE
SEE FOR HAVING AN APOE4 ALLELE
WHICH, AGAIN, HERE FOR
REFERENCE, KNOWN AS THE MOST
IMPORTANT GENETIC RISK FACTOR
FOR ALZHEIMER'S DISEASE.
AFIB, ANOTHER IMPORTANT VASCULAR
RISK FACTOR HIGHLY ASSOCIATED
WITH RISK OF STROKE.
IN THIS PARTICULAR STUDY,
ANOTHER LARGE EPIDEMIOLOGIC
COHORT SHOWING THAT THE
DIAGNOSIS AND INCIDENCE OF
ATRIAL FIBRILLATION IS
ASSOCIATED WITH A STEEPER
DECLINE IN COGNITION.
HERE IS SORT OF AN EXPECTED
AGE-EXPECTED DECLINE, STEEPER
DECLINE IN COGNITION AFTER
DIAGNOSIS OF AFIB, INDEPENDENT
OF CLINICAL STROKE.
SO THIS IS NOT COUNTING PEOPLE
WHO HAD A STROKE FROM THEIR AFIB
AND THAT'S WHY THEY DECLINED,
BUT RATHER HAD COGNITIVE CHANGE
REGARDLESS OF THAT KIND OF A
STROKE.
WHAT ABOUT DEMENTIA?
SO I MENTIONED THAT IT'S
IMPORTANT TO THINK NOT ONLY
ABOUT COGNITIVE CHANGE BUT
INCIDENT DEMENTIA FOR TREATMENT
FOLLOWING AN ARIC COHORT.
THESE ARE ALSO LOOKING FROM THE
ARIC STUDY WHERE WE LOOKED TET
ENTIRE COHORT AND LOOKED AT
ASSOCIATION WITH INCIDENT
DEMENTIA OVER 25-YEAR FOLLOW-UP.
THESE ARE ADJUSTED FOR EACH
OTHER AS WELL AS BASIC
DEMOGRAPHICS AND APOE STATUS.
BASICALLY WE FOUND AS EXPECTED
SOME OF THESE RISK FACTORS AND
VERY STRONG RELATIONSHIPS WITH
INCIDENT DEMENTIA.
SMOKING, 40% INCREASED HAZARD
OVER THESE YEARS.
DIABETES, THIS IS A HUGE EFFECT
SIZE IN MY OPINION.
NEARLY DOUBLING THE RI RISK.
DIABETES IS SOMETHING WE CAN
POTENTIALLY DO SOMETHING ABOUT,
TREAT AND PREVENT.
THIS IS REALLY IMPORTANT AS WE
THINK ABOUT PUBLIC HEALTH
MESSAGING.
HYPERTENSION, INCREASED RISK, WE
ALSO SAW AN INCREASED RISK OF
WHAT WAS THEN CALLED
PRE-HYPERTENSION IS NOW CALLED
STAGE I HYPERTENSION ASSOCIATED
WITH INCREASED DEMENTIA RISK.
INTERESTINGLY IN THAT STUDY, WE
DID SEE INCREASED DEMENTIA WITH
OBESITY AND TOTAL CHOLESTEROL
BUT OTHERS SUPPORTED THOSE RISK
FACTORS.
THE OTHER THING TO CONSIDER IS
NOT JUST VASCULAR HEALTH IN MID
LIFE, BUT HOW IT CHANGES OVER
THE LIFE COURSE.
SO MID LIFE IS CERTAINLY WHAT WE
THINK IS VERY IMPORTANT IN
UNDERSTANDING LATE LIFE BRAIN
HEALTH RISKS.
BUT THINGS CHANGE OVER THE LIFE
COURSE, SOMETIMES DEUM TO A, SOT
BLOOD PRESSURE TRAJECTORIES OVER
THE LIFE COURSE FROM MID LIFE TO
LATE LIFE AND INCIDENT DEMENTIA.
AFTER PHTHALATE LIFE
MEASUREMENT.
WHAT WE FOUND, SO WE EXPECTED TO
SEE HYPERTENSION CONSISTENTLY
THROUGHOUT THE LIFE COURSE TO BE
ASSOCIATED WITH IN INCIDENT
DEMENTIA.
BUT WE ALSO FOUND HYPERTENSION
FOLLOWED BY HYPOTENSION, SO
PEOPLE WITH HIGH BLOOD PRESSURE
IN MID LIFE BUT LOW BLOOD
PRESSURE IN LATE LIFE.
IF ANYTHING, THIS IS THE TOP
LINE HERE THAT RISK HAVE EVEN
BEEN A LITTLE HIGHER THAN THE
HYPERTENSIVE GROUP.
SO HYPERTENSION FOLLOWED BY
HYPOTENSION DID APPEAR TO BE A
HARMFUL PATTERN IN THIS
OBSERVATIONAL DATA.
IT'S ESPECIALLY THE CASE FOR
PEOPLE WHO WERE YOUNGER AT THE
START OF FOLLOW-UP, WHICH MEANS
THEY WERE PROBABLY CLOSER TO MID
LIFE, FURTHER EMPHASIZING THE
IMPORTANCE OF THESE EARLIER LIFE
MEASURES.
OTHER IMPORTANT VASCULAR RISK
FACTORS.
MICHELLE
[OH LOOKED AT ATRIAL CARD
CACARDIOPATHY.
REALLY SHE WANTED TO UNDERSTAND
HOW ATRIAL CARD YOP THEE
DIAGNOSED BY ECHO DATA AS WELL
AS BIOMARKER DATA WAS ASSOCIATED
WITH INCIDENT DEMENTIA, AND
ACTUALLY FOUND IT WAS.
SO INDIVIDUALS WHO WERE
DEMENTIA-FREE AT ECHO BASELINE
AT THAT VISIT 5 WHEN WE WERE IN
OLDER AGE, HAD MORE INCIDENT
DEMENTIA IF THEY HAD ATRIAL
CARDIOPATHY.
WENDY WANG LOOKED AT THIS WITH
OTHER ECHO MEASURES AND
SIMILARLY FOUND MEASURES OF POOR
LEFT ATRIAL FUNCTION AND SIZE
WERE ASSOCIATED WITH DEMENTIA AS
WELL.
SO FURTHER INDICATIONS THAT
VASCULAR RISK, THESE WERE BOTH
INDEPENDENT OF UNDERLYING
DIABETES, HYPERTENSION, ET
CETERA, WHEN WE'RE THINKING
ABOUT VASCULAR CONTRIBUTIONS TO
DEMENTIA.
WHAT ABOUT STROKE?
SO CERTAINLY I'VE BEEN
HIGHLIGHTING VASCULAR RISK
FACTORS THAT ARE ALSO WELL-KNOWN
RISK FACTORS FOR STROKE OF THE
I'M A STROKE NEUROLOGIST SO
CERTAINLY I THINK ABOUT STROKE
AND HOW TO TREAT PEOPLE WITH
STROKE, I THINK ABOUT THE LONG
TERM CONSEQUENCES OF STROKE AS
WELL.
SO SILVIA KOTON SHOWED INCIDENT
STROKE WAS ASSOCIATED WITH
HIGHER RISK OF DEMENTIA BUT
WASN'T SURPRISING BUT NEVER
SHOWN IN THIS LONGITUDAL SETTING
BEFORE BUT SHE ALSO LOOKED AT
STROKE SEVERITY.
WE SEPARATE PEOPLE BY THIS BLACK
LINE LOOKING AT DEMENTIA-FREE
SURVIVAL, THE BLACK LINE IS
PEOPLE WHO NEVER HAD A STROKE.
WE ADJUDICATE OVER THE ENTIRE
STUDY FOLLOW-UP IN ARIC.
PEOPLE WHO HAD ONE STROKE BUT
WHAT I RECALL A MILD MODERATE
STROKE USING WHAT'S CALLED THE
NIH STROKE SCALE AND PEOPLE WHO
HAD ONE STROKE BUT IT WAS
MODERATE TO SEVERE.
YOU CAN CLEARLY SEE SEPARATION,
NOT JUST EARLY ON BUT OVER
CONTINUED FOLLOW-UP.
SIMILARLY, NOT ONLY ARE MORE
SEVERE STROKES POTENTIALLY WORSE
FOR YOUR RISK OF DEMENTIA, BUT
CURRENT STROKES APPEAR TO BE.
SO HERE SHE LOOKED AT PEOPLE WHO
HAD SORT OF ONE STROKE OR
MULTIPLE STROKES DEPENDING ON
THE SEVERITY AND REALLY THE
WORST WERE PEOPLE WHO HAD TWO OR
MORE STROKES WHICH AT LEAST ONE
OF THEM WAS IN THE MODERATE TO
SEVERE RANGE.
THIS IS A REALLY BIG INCREASE IN
HAZARD.
THIS IS INDEPENDENT OF ADJUSTING
FOR OTHER TIME BEARING
COVARIATES INCLUDING UNDERLYING
FACTORS FOR STROKE RISK ITSELF
SO THIS IS NOT █JUST TELLING US
MULTIPLE PEOPLE HAVING MULTIPLE
STROKES ALTHOUGH I THINK THAT IS
SOME OF WHAT WE'RE SEEING HERE,
BUT WE STILL SEE THIS VERY LARGE
INCREASE IN DEMENTIA RATES.
SO HOW DO WE THINK ABOUT
MECHANISM LINKING?
CERTAINLY THERE'S A FEW MAJOR
THINGS THAT I THINK ABOUT WHEN
I'M THINKING FROM AN
EPIDEMIOLOGIC STANDPOINT HOW CAN
I LINK THESE TOGETHER.
SO ONE IS THAT VASCULAR RISK
FACTORS CAN LEAD TO STROKE.
THAT'S A CLINICAL VASCULAR EVENT
THAT CAN LEAD TO COGNITIVE
FINDING OF DEMENTIA.
I SHOWED YOU THE STRIVE
CONSORTIUM, DEFINITIONS OF SMALL
VESSEL DISEASE.
THOSE ARE SOME FORMS OF SILENT
VASCULAR IMPACT ON THE BRAIN.
THAT'S POSSIBLE THAT THAT'S THE
MECHANISTIC LINK BETWEEN
VASCULAR RISK AND COGNITIVE
DEMENTIA.
IT'S ALSO POSSIBLE THAT VASCULAR
RISK LEADS TO OTHER BRAIN
STRUCTURAL CHANGES, SO BRAIN
ATROPHY, FOR EXAMPLE.
AND THEN FINALLY, THERE'S A
POSSIBILITY THAT VASCULAR RISK
MIGHT DIRECTLY LEAD TO
ALTERATIONS IN ALZHEIMER'S
DISEASE NEUROPATHOLOGY AND THAT
IN TURN COULD -- AT THE
BEGINNING, IS THAT YOU HAVE TWO
COMMON PROCESSES WHICH ARE BOTH
IN TURN INCREASING YOUR RISK OF
A DIAGNOSIS AS DEMENTIA OR IT
MIGHT LEAD TO PATHOLOGIC
CHANGES.
SO HERE'S A SCHEMATIC SORT OF
THINKING ABOUT HOW WE TIE THESE
THINGS FOGHT.
TOGETHER.
THERE'S A LOT OF IMPORTANT RISK
FACTORS LISTED HERE.
WE KNOW THEY'RE ASSOCIATED WITH
DIFFERENT FORMS OF CEREBRAL
SMALL VESSEL DISEASE AND AGAIN
SOME OF THESE ARE SILENT
VASCULAR CHANGES IN THE BRAIN.
AND I COULD PUT SILENT IN COATS
BECAUSE THEY'RE VERY -- WITH
GATE DISTUR BABSS, INCREASED
RISK OF STROKE, ET CETERA, AND
LOOKING AT THESE OTHER
MECHANISMS THAT COULD TIE THESE
SMALL VESSEL DISEASE CHANGES AS
WELL AS THE RISK FACTORS TO
COGNITIVE DECLINE AND DEMENTIA.
SO LOOKING AT PART OF THE
RELATIONSHIP BETWEEN VASCULAR
RISK, SMALL VESSELS AND
COGNITIVE DECLINE BY
SPECIFICALLY FOCUSING ON THE
SMALL VESSEL DISEASE MARKERS.
AND WHAT SHE FOUND IS THAT IN
ARIC, PEOPLE WHO HAD MORE SILENT
CEREBROVASCULAR CHANGES AND
INFARCT IN THE BRAIN, AGAIN, NOT
CLINICAL STROKES BUT STROKE-LIED
CHANGES.
PEOPLE WHO HAD MORE OF THOSE
CHANGES AND YOU HAD BOTH OF
THOSE DIFFERENT TYPES OF CHANGES
HAD STEEPER COGNITIVE DECLINE
OVER 20 YEARS.
THIS WAS LOOKED AT IN OTHER
VASCULAR RISK FACTORS.
BLOOD PRESSURE, OTHER VASCULAR
RISK FACTORS WERE NOT ONLY
ASSOCIATED WITH MORE WHITE
MATTER HYPERINTENSITIES AS WELL
AS PROGRESSION, BUT ALSO A
DIFFUSION TENSOR IMAGING MEASURE
OF POOR WHITE MATTER INTEGRITY.
SO THIS IS FELT TO REALLY
CAPTURE SORT OF PREWHITE MATTER
HYPERINTENSITY IN THE PRAIN AND
TELLS US ABOUT AN EVEN EARLIER
STAGE IF YOU'RE TRYING TO
MECHANISTICALLY LINK WITH
VASCULAR CHANGES.
IN ADDITION, MELINDA ALSO LOOKED
AT THIS PATTERN OF HYPERTENSION
IN MID LIFE TO HYPOTENSION IN
LATE LIFE AND HOW IT RELATED TO
IMAGING MARKERS AND FOUND THOSE
PEOPLE HAD CERTAIN REGIONS IN
THE BRAIN THAT WERE SMALLER.
I MENTIONED ATROPHY, ALTERATIONS
IN BRAIN STRUCTURE, COULD BE ONE
ADDITIONAL WAY THAT -- PHYSICAL
ACTIVITY IN PARTICULAR AND ALSO
FOUND SOME ASSOCIATIONS WITH
SMALLER BRAIN VOLUMES,
ESPECIALLY IN THOSE REGIONS OF
THE PLAIN BRAIN THAT ARE
TYPICALLY INVOLVED IN
ALZHEIMER'S DISEASE.
SO WE TOOK THIS ONE STEP FURTHER
TO REALLY EP US UNDERSTAND HOW
MUCH OF A VASCULAR IMPACT
COGNITIVE DECLINE MIGHT BE
THROUGH SMALL VESSEL DISEASE AND
HOW MUCH MIGHT BE THROUGH BRAIN
ALTERATIONS AND STRUCTURE, SO
FOR INSTANCE, ATROPHY.
HE BASICALLY HYPOTHESIZED THAT
WHITE MATTER HYPERINTENSITIES,
INFARCTS WHICH ARE STROKE-LIKE
CHANGES BUT DIDN'T ACTUALLY
CAUSE STROKE SYMPTOMS AT THE
TIME, WERE SO SUITED WITH
COGNITIVE FUNCTION THAT WE
THOUGHT THAT RELATIONSHIP MIGHT
BE VALIDATED WILL, SO IN OTHER
WORDS WHEN WE SEE SMALLER BRAIN
VOLUMES IN A PATIENT, IS IT
BECAUSE THEY HAD A PRIOR
VASCULAR EVENT?
IN OTHER WORDS, WHEN WE SEE
VASCULAR RISK FACTOR
ASSOCIATIONS WITH ATROPHY, IS
THIS SIMPLY SAYING THERE WAS AT
SOME POINT A SMALL VESSEL
DISEASE MECHANISM LINKING THEM,
WE JUST CAN'T SEE THAT LATER
TIME POINT.
BASICALLY WHAT WE FOUND IS YES,
VASCULAR -- THE CEREBROVASCULAR
CHANGES IN THE BRAIN ARE
ASSOCIATED WITH WORSE COGNITION,
THIS DOMAIN POWER I TALKED ABOUT
EARLIER BUT AT LEAST PART OF
THAT RELATIONSHIP WAS -- SO
AGAIN, IMPLICATING VOLUME LOSS
AND LEASE TO PARTIALLY EXPLAIN
SOME OF THE MECHANISTIC LINK
BETWEEN CEREBROVASCULAR CHANGES
IN THE BRAIN THEMSELVES HIGHLY
ASSOCIATED WITH VAST LAR RISK
AND COGNITIVE PERFORMANCE.
AND THEN TO ANSWER THAT LAST
SORT OF MECHANISTIC QUESTION, I
HYPOTHESIZED THAT VASCULAR RISK
FACTORS COULD HAVE SOME DIRECT
IMPACT ON ALZHEIMER'S
NEUROPATHOLOGY.
SO I WANT TO MAKE A BRIEF ASIDE
BEFORE I SHARE THESE DATA WITH
YOU, I BY NO MEANS AM SUGGESTING
THAT AMYLOID DEPOSITION IS
SYNONYMOUS WITH ALZHEIMER'S
DISEASE.
CERTAINLY WE KNOW THAT AMYLOID
AND TAU ARE BOTH INCREDIBLY
IMPORTANT IN THE PATHOGENESIS OF
AD AND LEADING HYPOTHESES POINT
TO AMYLOID AS A MAJOR PLAYER AND
TO DATE CERTAINLY THAT'S BEEN
THE -- AND AT THE TIME, THE
DEVELOPMENT OF THE STUDY, IT WAS
THE AVAILABLE PET ISOTOPE WE
COULD LOCK AT AND REALLY LOOK AT
IN LIVING PEOPLE THAT WOULD HELP
US TO UNDERSTAND IN AN
OBSERVATIONAL STUDY SETTING THE
DIFFERENCE BETWEEN VASCULAR RISK
AND AN OPPENHEI -- THESE ARE ALE
WITHOUT DEMENTIA BY DESIGN FROM
THREE OF THE ARIC SITES.
SO WE LOOKED AT VASCULAR RISK
FACTORS IN MID LIFE AS WELL AS
IN LATER LIFE AND REALLY AGAIN
HERE THE QUESTION IS WAS THERE A
DIRECT LINK WITH PEOPLE THAT ARE
NOT DEMENTED IN THIS POPULATION
BETWEEN VASCULAR RISK AND
AMYLOID DEPOSITION.
AND IN GENERAL, WHEN WE LOOKED
AT MID LIFE RISK FACTORS, THE
GENERAL THEME WAS NO.
BUT WE DID SEE AN ASSOCIATION
BETWEEN MID LIFE RISK FACTORS
AND AMYLOID DEPOSITION IN LATER
LIFE ABOUT 20 YEARS LATER.
THERE WAS ONE EXCEPTION, OBES
OBESITY -- OTHER RISK FACTORS
INDEPENDENTLY WHEN WE LOOKED AT
EACH OF THEM SEPARATELY ADJUSTED
FOR EACH OTHER, ADJUSTED FOR
DEMOGRAPHICS, WERE NOT
ASSOCIATED WITH ELEVATED
AMYLOID.
SIMILARLY WHEN WE LOOK AT LATE
LIFE VASCULAR RISK FACTOR STATUS
WE DID NOT SEE ASSOCIATIONS FOR
ANY OF THEM WITH CONCURRENT
AMYLOID DEPOSITION.
SO INDIVIDUAL RISK FACTORS WITH
THE EXCEPTION OF BMI DID NOT
APPEAR IMPORTANT IN SUBS SUBSEQT
AMYLOID DEFINITION.
HOWEVER WHEN WE THOUGHT ABOUT
VASCULAR BURDEN IN A DIFFERENT
WAY WE SAW A SLIGHTLY DIFFERENT
STORY, AND THIS IS IMPORTANT AND
IN MY OPINION JUSTIFIABLE
BECAUSE MOST OF THESE VASCULAR
RISK FACTORS DON'T ACT BY
THEMSELVES, JUST LIKE THESE
UNDERLYING PATHOLOGIES DON'T ACT
BY THEMSELVES.
CERTAINLY PEOPLE WITH
HYPERTENSION MIGHT HAVE ANOTHER
RISK FACTOR AND SO ON.
SO WE DID A TALLEY OF HOW MANY
RISK FACTORS OUT OF THE SET OF
FIVE.
SO HIGH BLOOD PRESSURE,
DIABETES, OBESITY, HIGH
CHOLESTEROL AND SMOKING.
WE TALLEYED HOW MANY OF THOSE
PEOPLE HAD IN MID LIFE AND
LOOKED FOR ASSOCIATIONS WITH
AMYLOID IN LATER LIFE.
WHAT WE FOUND, IF YOU LOOKED AT
THE EARLIEST VISIT, THE CLOSEST
WE HAVE IN THIS COHORT, PEOPLE
WHO HAD ONE VASCULAR RISK FACTOR
IN MID LIFE AS COMPARED TO THOSE
WHO HAD NONE HAD NEARLY A
DOUBLING OF ODDS OF AMYLOID IN
THEIR BRAIN IN LATER LIFE AND IF
YOU HAD TWO OR MORE RISK
FACTORS, YOU HAD NEARLY A
TRIPLING OF ODDS OF AMYLOID IN
LATER LIFE ALONG WITH OTHER
DEMOGRAPHIC FACTORS.
AS YOU GET CLOSER TO -- VISIT
5 HERE, THAT ASSOCIATION GETS
WEAKER.
SO AGAIN, FURTHER EVIDENCE THAT
MID LIFE IS ESPECIALLY IMPORTANT
FOR ASSOCIATION WITH LATER LIFE
PATHOLOGIES, IN THIS CASE
AMYLOID DEPOSITION, AND
SOMETHING RESEMBLING A
DOSE-RESPONSE RELATIONSHIP
BETWEEN EXTENT OF VASCULAR RISK
IN LATE LIFE.
I ALSO WANT TO POINT OUT
SOMETHING WHICH IS IN MY OPINION
VERY RELEVANT TO SONJA'S TALK IN
THINKING ABOUT NOT JUST GENETIC
PATHOLOGIES OR CONTRIBUTIONS AND
VASCULAR CONTRIBUTIONS IN
ISOLATION, BUT HOW THEY PLAY A
ROLE TOGETHER.
SO IN THIS PARTICULAR STUDY, WE
LOOKED AT PEOPLE WHO HAD A HIGH
VASCULAR RISK AND WERE CARRIERS
OF AT LEAST ONE APOE 4 ALLELE,
THEIR RISK FOR AMYLOID WENT UP.
SO NINE FOLD INCREASED ODDS OF
HAVING ELEVATED AMYLOID IF UR
WERE AN E4 CARRIER AND HAD TWO
OR MORE VASCULAR RISK FACTORS IN
MID LIFE, AND IF YOU LOOK DOWN
HERE IN THE BOTTOM CORNER,
HYPERTENSION IF YOU LOOKED AT
SYSTOLIC BLOOD PRESSURE
CONTINUOUSLY, IT LOOKS AS THOUGH
THE RELATIONSHIP BETWEEN MID
LIFE BLOOD PRESSURE AND LATER
LIFE AMYLOID DEPOSITION IS
NON-EXISTNON-EXISTENT IF YOU ONN
PEOPLE WITHOUT E FOR ALLELE BUT
IF YOU LOOK IN CARRIERS, IT
SUGGESTS THERE'S RELATIONSHIP
TWEENL THE TWO.
SO THIS IN MY OPINION IS
EVIDENCE THERE'S SOME TWO-BIT
PROCESS POTENTIALLY GOING ON HEE
AND AGAIN WE NEED TO THINK ABOUT
WHO IS AT HIGHEST RISK BUT ALSO
HOW MANY DIFFERENT ANGLES DO WE
NEED TO APPROACH THIS DISEASE IF
WE'RE UNDERSTANDING INTERACTIONS
BETWEEN VASCULAR RISK AND
GENETIC RISK AS WELL.
FURTHER EVIDENCE, KENAN WALKER
LOOKED AT THIS FOR WHITE MATTER
HYPERINTENSITIES AND AMYLOID
DEPOSITION.
I MENTIONED AS A FORM OF SMALL
VESSEL DISEASE ARE HIGHLY
ASSOCIATED WITH VASCULAR RISK
FACTORS.
WE LOOKED A AT THEM CONCURRENT
WITH AMYLOID DEPOSITION AND
FOUND THAT IN GENERAL, AMYLOID
DEPOSITION WAS ELEVATED IN
PEOPLE WHO HAD MORE WHITEWATER
HYPERINTENSITIES HELPING US TO
TRY TO UNDERSTAND THE
MECHANISTIC LINK HERE IN THIS
NON-DEMENTED COHORT AND IF
ANYTHING, THE ASSOCIATION IS
STRONGER IN BLACK THAN WHITE
PARTICIPANTS.
SO WHAT ABOUT THIS MODIFIABLE
RISK?
SO I HOPE THAT I'VE MADE A CASE
THAT VASCULAR RISK FACTORS ARE
ASSOCIATED WITH COGNITIVE
DECLINE AND DEMENTIA.
I HOPE THAT I'VE CONVINCED YOU
THAT THERE'S SOME EVIDENCE
MECHANISTICALLY LINKING THESE
TOGETHER.
AND THAT WE REALLY NEED TO THINK
ABOUT MULTIPLE PROCESSES WHEN
WE'RE TRYING TO UNDERSTAND
COGNITIVE FINDING IN PATIENTS.
THE LANCET COMMISSION REALLY DID
A WONDERFUL JOB IN MY OPINION,
TRYING TO ESTIMATE HOW MUCH
DEMENTIA RISK WAS POTENTIALLY
MODIFIABLE.
YOU CAN SEE HERE THIS GRAPHIC
THIS PUBLISHED, THIS IS THE
UPDATE IN 2020, BEAUTIFULLY
THINKS ABOUT MODIFIABLE RISK
OVER THE LIFE COURSE.
SO HERE THEY EMPHASIZE IN EARLY
LIFELESS EDUCATION IS AN
IMPORTANT RISK FACTOR, AND IN
THESE CIRCLES THEY SHOW THE
PERCENT DEMENTIA CASES THAT THEY
THINK ARE MODIFIABLE
CONTRIBUTING TO THAT RISK
FACTOR.
SO CERTAINLY IF WE SEE
HYPERTENSION IN MID LIFE,
DIABETES IS HERE, I WOULD ARGUE
IT'S ALSO IMPORTANT IN MID LIFE.
I'M NOT GOING TO SPEND TIME
TALKING ABOUT REALLY IMPORTANT
RISK FACTORS SUCH AS HEARING
LOSS, SOCIAL ISOLATION I'LL TALK
ABOUT VERY BRIEFLY, BUT REALLY
THIS IS I THINK AN IMPORTANT WAY
TO THINK ABOUT MODIFIABLE RISK.
MARK LEE AT UNIVERSITY OF
MINNESOTA LOOKED AT RISK FACTORS
IDENTIFIED -- ESTIMATED THAT
ABOUT 41% OF CASES OF DEMENTIA
IN THE U.S. ARE ATTRIT UTABLE TO
THESE 12 MODIFIABLE RISK
FACTORS.
THE STRONGEST ATTRIBUTABLE RISKS
WERE FOR HYPERTENSION, OBESITY
AND PHYSICAL INACTIVITY.
AND REALISTICALLY WE KNOW WE
CAN'T MAKE THESE RISK FACTORS GO
AWAY COMPLETELY.
BUT THE ESTIMATE WAS THAT IF WE
COULD REDUCE EACH OF THEM BY
15%, THAT WE COULD REDUCE
DEMENTIA RATES BY ABOUT 7%.
I DO WANT TO MAKE AN IMPORTANT
POINT, THE POPULATION
ATTRIBUTABLE RISK OF 41% IS
HIGHER IF WE LOOK AT MINORITIZED
POPULATIONS.
SO 46% FOR BLACK AMERICANS, 47%
FOR LATINX AMERICANS.
SO THESE REALLY IMPORTANT
MODIFIABLE RISK FACTORS BROADLY
BUT ALSO UNDERSTANDING SOME OF
THE DISPARITIES ASSOCIATED WITH
DISEASES SUCH AS DEMENTIA.
SO WHAT ABOUT THE ACTUAL
EVIDENCE THAT TREATING THESE
RISK FACTORS MIGHT MAKE A
DIFFERENCE?
SO I'VE SHARED OBSERVATIONAL
EPIDEMIOLOGIC DATA, AND IN
GENERAL, THERE AREN'T A HUGE
AMOUNT OF DATA THAT SHOW US THAT
ACTUALLY TREATING THESE RISK
FACTORS REDUCES RISK AND LEADS
TO LESS COGNITIVE DECLINE AND
DEMENTIA.
THE SPRINT STUDY WAS ONE STUDY
THAT SORT OF CAME CLOSE TO
SHOWING A POSITIVE IMPACT OF AN
INTERVENTION.
SO SPRINT WAS A TRIAL LOOKING AT
BLOOD PRESSURE CONTROL, STANDARD
BLOOD PRESSURE CONTROL VERSUS
MORE INTENSIVE BLOOD PRESSURE
CONTROL TO BRING SYSTOLICS BELOW
120.
THE STUDY WAS DESIGNED TO LOOK
AT CARDIOVASCULAR END POINTS AND
THEY DID AN AMAZING JOB AT
ACHIEVING A GREAT DELTA BETWEEN
THEIR TWO BLOOD PRESSURE GROUPS.
THE STUDY WAS STOPPED EARLY FOR
AN OVERWHELMING CARDIOVASCULAR
BENEFIT BUT THE SECOND STUDY,
SPRINT-MIND, WAS THEREFORE NOT
ABLE TO ACCRUE AS MUCH TIME AS
MIGHT HAVE BEEN INITIALLY
PLANNED.
SPRINT-MIND WAS DESIGNED TO LOOK
AT DIFFERENCES IN DEMENTIA RATE
AND ALTHOUGH THERE'S A
SUGGESTION OF A DIFFERENCE HERE,
THEY DID NOT ACHIEVE THEIR
PRIMARY OUT COME SHOWING LESS
DEMENTIA IN PEOPLE WITH THE MORE
INTENSIVE BLOOD PRESSURE CONTROL
VERSUS PEOPLE WITH THE MORE
STANDARD BLOOD PRESSURE CONTROL.
THEY DID SHOW LESS MCI AND LESS
COMPOSITE MCI AND DEMENTIA WITH
SORT OF CONSISTENT EFFECT SIZES
HERE, YOU CAN SEE THE CURVE
SEPARATING, BUT IN GENERAL, THIS
IS A RELATIVELY SHORT PERIOD OF
FOLLOW-UP.
WHICH IS REALLY AN IMPORTANT
THING TO THINK IN MIND.
I'VE SHARED WITH YOU I THINK MID
LIFE IS ESPECIALLY IMPORTANT IN
UNDERSTANDING RISK OF SUBSEQUENT
COGNITIVE DECLINE, AND DEMENTIA,
AND THIS IS A STUDY OF PEOPLE
GENERALLY IN OLDER AGE THAT
FOLLOWED THEM FOR FOUR YEARS,
IT'S LESS LIKELY THAT WE'RE
GOING TO SEE A BENEFIT OF
INTENSIVE BLOOD PRESSURE CONTROL
OVER THAT PERIOD OF TIME OF WHAT
ABOUT OTHER MODIFICATIONS OF
RISK OF DEMENTIA?
SO THE ASPREE TRIAL LOOKED AT
THE ROLE OF ASPIRIN, NOT PEOPLE
WITH PRIOR STROKE OR
CARDIOVASCULAR DISEASE AND
LOOKED AT IMPACT OF ASPIRIN USE
IN THAT SETTING, THESE CURVES
LOOK COMPLETELY SUPERIMPOSED AND
THEY BASICALLY ARE STATIS
STATISTICALLY.
IN GENERAL THAT'S A GENERALLY
LOWER RISK POPULATION.
BUT STILL, NOT EVIDENCE THAT
TREATING OR PREVENTING STROKE
WHICH IS A WAY THAT WE THINK
ABOUT RISK FACTORS AND
MODIFIABLE RISK IS ACTUALLY
GOING TO HAVE IMPACT ON
PREVENTING DEMENTIA.
THE MULTIMODAL, THERE'VE BEEN A
SERIES OF MULTIMODAL TRIALS THAT
APPEAR TO BE A LITTLE BIT MORE
PROMISING.
SO THE FINGER TRIAL WAS A STUDY
THAT RANDOMIZED PEOPLE TO A
TWO-YEAR MULTIDOMAIN
INTERVENTION WHICH WAS A
COMPOSITE OF VAST LAR RISK
FACTOR CONTROL MONITORING,
CLOCKTIVE TRAINING, DIET AND
EXERCISE, AND VERSUS A SORT OF
STANDARD CONTROL GROUP THAT
STILL HAD FOLLOW-UP VISITS.
OVER TWO YEARS THEY SAW LESS
COGNITIVE CHANGE IN THE
INTERVENTION GROUP AS COMPARED
TO THE CONTROL, AND THIS IS
REALLY BEEN EXPANDED INTO A
SERIES OF STUDIES.
IN THE U.S. THERE'S ONE CALLED
U.S. POINTER, THEY'RE ALL FINGER
THEMES, WORLDWIDE FINGERS IS THE
INTERNATIONAL CONSORTIUM OF ALL
OF THESE DIFFERENT TRIALS.
WHAT I THINK IS THE REALLY COOL
THING ABOUT ALL OF THESE STUDIES
IS EACH COMPONENT OF WORLDWIDE
FINGERS IS ADAPTING THE CONCEPT
OF A MULTIMODAL INTERVENTION TO
A CULTURALLY APPROPRIATE
SETTING, SO FOR EXAMPLE, FINGER
WAS IN FINLAND AND THE DIETARY
INTERVENTIONS WERE VERY
HERRING-BASED AND DIETARY SORT
OF MO MODIFICATIONS THAT WOULDNT
NECESSARILY TRANSLATE AS WELL TO
A DIFFERENT CULTURE, SO REALLY
THERE'S BEEN AN EMPHASIS ON
THINKING ABOUT HOW TO ADAPT THIS
TO MAKE A MEANINGFUL MULTIDOMAIN
INTERVENTION THAT CAN BE TESTED
IN DIFFERENT CULTURES AND ALL
OVER THE WORLD.
SO WHY IS IT THAT WE'RE SEEING
PRETTY STRONG EVIDENCE FROM THE
EPIDEMIOLOGY SIDE BUT NOT SEEING
SUCCESSFUL INTERVENTIONS FOR
BRAIN HEALTH.
SO ONE IS WHAT I ALREADY
MENTIONED.
MOST TRIALS ARE SIMPLY NOT LONG
ENOUGH TO REALLY GET AT THIS
LIFE COURSE RISK FACTORS ON
COGNITIVE DECLINE AND DEMENTIA.
SO REALISTICALLY NO ONE IS GOING
TO FUND A 30-YEAR TRIAL LOOKING
AT SOME INTERVENTION OVER THAT
TIME PERIOD TO SEE IF IT AFFECTS
COGNITIVE DECLINE AND DEMENTIA.
IN ADDITION, PEOPLE CAN BE
OUTLIERS, SO IT'S POSSIBLE THAT
A POPULATION BASED APPROACH
DOESN'T REALLY APPLY WHEN YOU'RE
THINKING ABOUT INDIVIDUALS, AND
THEN IT MAY BE THAT VASCULAR
HEALTH HAS DIFFERENT IMPACTS IN
DIFFERENT PEOPLE.
AND I JUST WANT TO SPEND THE
LAST COUPLE MINUTES OF MY PART
OF THE TALK TOUCHING ON A FEW
DIFFERENT IMPORTANT
CONSIDERATIONS.
SO THERE MAY BE OTHER FACTORS
THAT REALLY ARE IMPORTANT FOR
BRAIN HEALTH THAT WE'RE NOT
THINKING ABOUT WHEN WE'RE
THINKING ABOUT HOWL TO ADAPT
THESE OBSERVATIONAL DATA TO A
TRIAL SETTING OR TO AN
INTERVENTIONAL SETTING.
SO ONE IS A CONCEPT OF COGNITIVE
RESERVE WHICH I'M GOING TO
DEFINE IN A MOMENT.
ANOTHER IS IN GENERAL HOW WE
THINK ABOUT HEALTH PROMOTING
LIFESTYLE FACTORS AND THAT TIES
IN WITH COGNITIVE RESERVE, AND
THEN BRIEFLY I WANT TO WRAP UP
TALKING ABOUT INTERACTIONS WITH
GENETICS AND OTHER PATHOLOGIES
CERTAINLY TO TRY TO TIE BACK IN
WITH SONJA'S BEAUTIFUL TALK.
SO KILOGRAMTIVE RESERVE IS THE
IDEA THAT SOMEONE'S COGNITIVE
FUNCTION IS BETTER THAN EXPECTED
DESPITE UNDERLYING BRAIN
PATHOLOGY.
SO WE KNOW THAT THIS HAS BEEN
SHOWN IN MULTIPLE STUDIES, DAVID
BENNETT PUBLISHED THESE DATA
AGAIN FROM THE RELIGIOUS ORDER
STUDY SET OF PATHOLOGY DATA THAT
I SHARED THE DATA EARLIER, BUT
IN GENERAL WE EXPECT SOMEONE TO
BE AT A CERTAIN LEVEL BUT SOME
FACTOR MAKES THEM PERFORM BETTER
THAN EXPECTED.
SO EDUCATION IS THE CLASSIC
EXAMPLE OF THE FORM OF COGNITIVE
RESERVE THAT WE WOULD EXPECT BY
SOMEONE'S PATHOLOGY IN THEIR
BRAIN THAT THEIR PERFORMANCE
WOULD BE AT A CERTAIN LEVEL,
PEOPLE OF HIGHER EDUCATION
APPEAR TO PERFORM AT A HIGHER
LEVEL THAN EXPECTED.
SO WE KNOW THAT EARLY LIFE EVEN
BEFORE THAT MID LIFE PERIOD THAT
I TALKED ABOUT, THERE'S GOOD
EVIDENCE THAT COGNITIVE RESERVE,
THINGS THAT HAPPEN TO
INDIVIDUALS IN EARLY LIFE MAY BE
VERY IMPORTANT IN GIVING THEM
THAT RESERVE AND THAT RESILIENCE
TO NEUROPATHOLOGY.
SO HERE IS EVIDENCE BETTER
CHILDHOOD GRADES ASSOCIATED WITH
LOWER RISK OF DEMENTIA.
THE EPIDEMIOLOGISTS IN THE
AUDIENCE SAY THAT COULD BE
MASSIVELY CONFOUNDED BY SO MANY
DIFFERENT FACTORS AND CERTAINLY
THAT'S GOING TO BE THE CASE FOR
A LOT OF THESE WHICH MAKES THESE
SORT OF HARD TO STUDY.
HIGHER CHILDHOOD IQ ASSOCIATED
WITH LOWER DEMENTIA RATES.
TEENAGERS WITH MORE PHYSICAL
ACTIVITY SO LIFESTYLE PROMOTING
BEHAVIORS ASSOCIATED WITH
DELAYED COGNITIVE DECLINE IN
MULTIPLE STUDIES, AND THEN THE
FAMOUS NUN STUDY, LINGUISTIC
COMPLEXITY, WHICH WAS -- SO A
SERIES OF NUNS, THEIR DIARIES
WERE REVIEWED FOR THE LINGUISTIC
COMPLEXITY AND THOSE WHO HAD
LESS LINGUISTIC COMPLEXITY IN
THESE DIARIES THAT THEY KEPT
WHEN THEY WERE IN THEIR EARLY
20s HAD A MORE LATE LIFE
ALZHEIMER'S DISEASE.
SO EVIDENCE THAT THINGS THAT
PEOPLE DO EARLY ON AND THEIR
ABILITY TO SORT OF INTERACT
EARLY ON MAY BE REALLY IMPORTANT
FOR HOW THEY PERFORM LATER OVER
TIME.
I WANT TO BRIEFLY MENTION AN
ONGOING STUDY, RENEE LOOKED
SPECIFICALLY AT SOCIAL
ENGAGEMENT IN THE ARIC COHORT.
SO WE HAVE MEASURES OF SOCIAL
ISOLATION AND SOCIAL SUPPORT IN
ARIC AND SHE'S COME UP WITH A
COMPOSITE SOCIAL ENGAGEMENT
MEASURE IN MID LIFE AND LOOKING
AT RELATIONSHIPS WITH INCIDENT
DEMENTIA OVER TIME, AND IN
GENERAL, YOU CAN SEE HERE PEOPLE
WHO HAVE STRONG SOCIAL
ENGAGEMENT VERSUS POOR SOCIAL
ENGAGEMENT WHERE THIS IS NEN
DEMENTIA-FREE SURVIVAL, THOSE
WITH STRONG SOCIAL ENGAGEMENT DO
BETTER THAN THOSE WHO HAD POOR
SOCIAL ENGAGEMENT.
AND HERE ARE THE HAZARDS FOR
STRONG SOCIAL RELATIONSHIPS AS
COMPARED TO POOR VERSUS AVERAGE.
SO AGAIN, SORT OF A
DOSE-RESPONSE KIND OF
RELATIONSHIP POINTING TO THE
IMPORTANCE OF THIS OTHER
POTENTIAL FORM OF COGNITIVE
RESERVE.
AND THIS IS INDEPENDENT OF
GENETICS, NOT MODIFIED BY JE NE
AT THE RICK IGENETIC RISK EITHE.
PEOPLE WITH JOBS WITH HIGHER
INFORMATION PROCESSING ARE
ASSOCIATED WITH LOWER DEMENTIA
RATES OVER TIME.
I MENTIONED THAT EDUCATION IS
ONE OF THE MOST COMMON ONES, BUT
I THINK WE NEED TO THINK ABOUT
THESE FACTORS IN ADDITION TO
THESE ADDITIONAL PATHOLOGIES
THAT WE SEE WHICH ARE OFTEN
OVERLAID.
SO WHAT ABOUT HOW GENETIC RISK
TIES IN.
I WANT TO BRING IT BACK TO WHAT
SONJA TALKED ABOUT A BIT.
SO HERE'S A STUDY IN THE UK
BIOBANK WHICH CATEGORIZED BOTH A
POLYGENIC RISK, SO USING A
CLASSIC DEMENTIA POLYGENIC RISK
SCORE AS HAS BEEN DESCRIBED FOR
ALZHEIMER'S DISEASE, AS WELL AS
WHAT THEY CALL THE POLYSOCIAL
RISK, SO AGAIN, THIS IS GETTING
AT FACTORS LIKE I JUST TALKED
ABOUT, SOCIAL ISOLATION,
EDUCATION, AND HERE THEY SORT OF
CAPTURED PEOPLE WITH BOTH HIGH
RISK AND LOW RISK, BUT THEY
FOUND IN GENERAL THAT EVEN IF
YOU HAVE A HIGH GENETIC RISK, SO
YOUR POLYGENIC RISK SCORE WAS
ELEVATED SO YOU HAD A HIGH
GENETIC RISK TO ALZHEIMER'S
DISEASE AND HERE THEY HAVE WHAT
THEY CLASSIFY AS ALL CAUSE
DEMENTIA ALZHEIMER'S DISEASE AND
VASCULAR DEMENTIA, AND AGAIN I
WOULD ARGUE THAT MEAN MANY OF E
CASES ARE MIXED PATHOLOGY BUT IF
YOU'RE AT THE HIGHEST GENETIC
RISK, YOUR SOCIAL RISK IS LOWER,
THAT REDUCED YOUR RISK OF
DEMENTIA.
SO OBSERVATIONAL DATA OBVIOUSLY
BUT IT SUGGESTS IF YOUR GENETIC
RRISK IS HIGH -- ADRIENNE TIN DD
THIS WORK AT UNIVERSITY OF
MISSISSIPPI MEDICAL CENTER AND
LOOKED AT THE LIFE SIMPLE SEVEN
SCORE.
THIS IS A MEASURE THAT THE
AMERICAN HEART ASSOCIATION
DESCRIBED WHICH WAS A MEASURE OF
OPTIMAL IDEAL CARDIOVASCULAR
HEALTH.
THEY'VE SINCE UPDATED TO THE --
THERE'S EIGHT COMPONENTS NOW,
BUT THE LIFE SIMPLE SEVEN
CAPTURED -- A HIGHER SCORE IS
BETTER CARDIOVASCULAR HEALTH AND
BASICALLY SHE FOUND A SIMILAR
RESULT, WHICH IS THAT LOOKING AT
A POLYGENIC RISK SCORE IN BOTH
BLACK AND WHITE ADULTS, THAT
EVEN IN PEOPLE WITH A HIGH
GENETIC RISK, THAT HAVING IDEAL
CARDIOVASCULAR HEALTH REDUCED
YOUR RISK OF DEMENTIA.
SO HERE IS SORT OF TOP GENETIC
RISK HERE, THE HIGHEST QUINTILE
HERE, TOP GENETIC RISK, YOU CAN
SEE THAT HAVING HIGH LIFE SIMPLE
SEVEN HAD A REDUCTION IN -- I'M
SORRY, THIS IS THE HIGHEST
GENETIC RISK SCORE IN ALL
GENETIC STRATA HAVING A HIGHER
LIFE SIMPLE SEVEN WAS ASSOCIATED
WITH REDUCED RISK OF INCIDENT
DEMENTIA.
NAD, OTHER PATHOLOGIES ARE
OBVIOUSLY GOING TO PLAY A ROLE.
WE TALKED ABOUT THE OVERLAP
BETWEEN ALZHEIMER'S DISEASE AND
VASCULAR HEALTH AND CERTAINLY
BETWEEN ALZHEIMER'S DISEASE,
VASCULAR HEALTH AND LEWY BODY
DEMENTIA AND OTHER
NEURODEGENERATIVE CONDITIONS.
IN THIS STUDY, WE WANTED TO
UNDERSTAND HOW DIFFERENT
PATHOLOGIES MIGHT ACTUALLY
CONTRIBUTE TO DEMENTIA.
I MENTIONED EARLIER THAT I
THOUGHT THAT HAVING BOTH
VASCULAR DISEASE AND ALZHEIMER'S
NEUROPATHOLOGY MOST LIKELY MIGHT
INCREASE YOUR RISK OF DEMENTIA
BUT THERE MIGHT BE SOME DIRECT
LINK BETWEEN THEM AS WELL AS
SUGGESTED BY OUR ARIC PET DATA,
BUT IN THIS STUDY WE LOOKED AT
ASSOCIATIONS BETWEEN VASCULAR
RISK AS WELL AS WHITE MATTER
HYPERINTENSITIES AND LATER LIFE
MEASURE THAT MIGHT LINK VASCULAR
RISK WITH DEMENTIA AND AMYLOID
AND BASICALLY FOUND THAT
HYPERTENSION AND AMYLOID EACH
INDEPENDENTLY WERE ASSOCIATED
WITH INCIDENT DEMENTIA RISK
MEASURED AFTER THE POINT OF THE
PET SCAN, AND ACTUALLY THEY BOTH
HAD A VERY LARGE RISK, AND THIS
IS LOOKING AT MID LIFE VASCULAR
RISK FACTOR, SO HYPERTENSION IN
MID LIFE WAS ASSOCIATED WITH
MORE THAN A DOUBLING INDEPENDENT
OF AMYLOID, INDEPENDENT OF
DEMOGRAPHICS AND OTHER RISK
FACTORS, AFTER VISIT FIVE AND
THIS IS ALSO INDEPENDENT OF APOE
I'LL ADD, BUT THESE DID NOT
INTERACT ON A MULTIPLICATIVE
SCALE.
EACH WAS ASSOCIATED WITH A I
HAOER RISK OF DEMENTIA BUT NOT
AS INCREASED AS WE THOUGHT IT
MIGHT BE IN THE PRESENCE OF
THESE TWO PATHOLOGIES TOGETHER.
SO I WANT TO BRING THESE POINTS
TOGETHER.
I THINK AS WE THINK ABOUT
GENETICS, AS WE THINK ABOUT
UNDERLYING PROCESSES LEADING TO
NEURODEGENERATION AND AS WE
THINK ABOUT CARDIOVASCULAR RISK,
THIS IS GOING TO IDENTIFY MORE
PEOPLE WHO ARE PROBABLY AT HIGH
RISK.
SONJA MAILED THE POINT THAT ONE
ADVANTAGE OF HAVING DISEASES
WITH MIXED PATHOLOGIES AND
OVERLAPPING MECHANISMS, WE CAN
TAKE WHAT WE LEARN FROM ONE AND
APPLY TO THE OTHERS.
I WOULD ALSO ARGUE THAT THERE'S
A POTENTIAL DANGER IF WE SPEND A
LOT OF TIME LEARNING HOW TO
TREAT ONE UNDERLYING PATHOLOGY
OR ONE NEURODEGENERATIVE PROCESS
AND IGNORE THE OTHER COMPONENTS
SUCH AS VASCULAR RISK AND WE'RE
NOT GOING TO REALLY SOLVE THE
PROBLEM ENTIRELY.
SO I THINK IT'S REALLY IMPORTANT
TO THINK ABOUT WAYS THAT WE CAN
MODIFY RISK FROM SEVERAL
DIFFERENT ANGLES, AND THIS
REALLY NICE REVIEW SORT OF MAKES
THIS POINT, THAT THERE'S PEOPLE
WHO MIGHT BE PARTICULARLY HIGH
RISK THAT ARE AT A GENETIC RISK
BUT PARTICULARLY IN COMBINATION
WITH CARDIOVASCULAR RISK, YOU
REALLY HAVE TO THINK ABOUT WHO
WE MIGHT TARGET PREVENTION
STRATEGIES.
SO IN CONCLUSION, MOST DEMENTIAS
ARE DUE TO MIXED PATHOLOGY.
VASCULAR RISK FACTORS ARE IN MY
OPINION A REALLY IMPORTANT
MODIFIABLE TARGET TO DEMENTIA
PREVENTION DESPITE THE LACK OF
CONSISTENT RESULTS IN ACTUAL
CLINICAL TRIALS, MUCH DUE TO THE
IMPORTANCE OF MID LIFE AND
LOOKING AT THE WHOLE LIFE
PERSON, UNDERSTANDING THE
COMBINATION OF VASCULAR RISK.
MECHANISTICALLY, THE
EPIDEMIOLOGIC DATA SUGGESTS
THATTALITY RAIGS IN BRAIN SUCK
TREUR FUNCTION AND MAYBE EVEN
AMYLOID PRODUCTION -- AND THEN
IN ADDITION, THIS POINT ABOUT
GENETIC RISK MIGHT FURTHER
INCREASE -- CERTAIN LE WE KNOW
THE GENETIC RISK IS GOING TO
CONTRIBUTE TO RISK FOR DEMENTIA,
BUT IT MAY BE THAT THERE'S A
COMBINATION OF VASCULAR AND
GENETIC COMPONENTS WE NEED TO
THINK ABOUT AND ALSO AS WELL AS
THINKING ABOUT THINGS LIKE WHAT
CONTRIBUTES TO COGNITIVE RESERVE
AND SOCIAL FACTORS AS THESE ALL
CLEARLY HAVE AN INTERPLAY.
IN GENERAL, THIS LAST POINT IS
THE POINT THAT I JUST MADE,
WHICH IS AS WE CONTINUE TO THINK
ABOUT TREATMENT OPTIONS, AND
CERTAINLY THERE'S A FOCUS ON
TREATMENT OPTIONS FOR AD, WE
CAN'T IGNORE THESE OTHER
ASPECTS, BECAUSE MOST
PATHOLOGIES, MOST DEMENTIAS ARE
MIXED AND TREATING ONE PART OF
IT IS NOT GOING TO TREAT THE
WHOLE PROBLEM, NOR IS IT GOING
TO TREAT EVERYONE WHO HAS A
DEMENTING DISORDER.
WE ALSO NEED TO THINK ABOUT
MODIFYING NOT ONLY VASCULAR RISK
BUT ALSO WAYS TO AUGMENT
COGNITIVE RESERVE IN DIVERSE
POPULATIONS.
HERE'S MY ACKNOWLEDGMENTS.
MY WORK IS ABSOLUTELY VERY MUCH
TEAM SCIENCE, AS IS SONJA'S, AND
I'VE HAD SOME ABSOLUTELY
WONDERFUL COLLEAGUES THAT I'VE
HAD THE OPPORTUNITY TO WORK WITH
OVER TIME, CERTAINLY
ACKNOWLEDGING THE ARIC
PARTICIPANTS AND STAFF AND MY
FUNDING WITH THE INTRAMURAL
RESEARCH PROGRAM AT NINDS.
HERE WE ARE IN VARIOUS FORMS,
AND WITH THAT, I WILL STOP, AND
I'M HAPPY -- LOOKING FORWARD TO
THE DISCUSSION THAT SONJA AND A
I CAN HAVE WITH THE REST OF YOU.
SO THANK YOU VERY MUCH.
>> ALL RIGHT.
WELL, I CAN ONLY SAY, HOLY
MACKEREL, THAT WAS REALLY
SOMETHING.
THE ONE-TWO PUNCH OF DRS. SCHOLZ
AND GOTTESMAN.
THAT WAS FASCINATING AND
INCREDIBLY STIMULATING.
WE HAVE LOTS AND LOTS OF
QUESTIONS FROM THE ONLINE
AUDIENCE.
SO ONE OF THEM THAT CAME UP THAT
I DON'T THINK WAS COVERED BY
EITHER OF OUR TWO SPEAKERS IS
THE -- AND MAYBE IT'S BECAUSE
THERE ISN'T ANYTHING, BUT IS THE
ROLE OF GENDER.
AND WHETHER THERE ARE ANY
DIFFERENCES BETWEEN MEN AND
WOMEN IN TERMS OF THEIR RISK OF
DEMENTIA, AND FOR THAT MATTER,
ARE THERE ANY DIFFERENCES IN
TERMS OF INTERVENTIONS THAT ONE
MIGHT CONSIDER BETWEEN MEN AND
WOMEN?
>> I CAN GET STARTED AND THEN
REBECCA CAN ADD ON.
SO YES, WE ARE ACTUALLY -- SEE
DIFFERENCES IN BOTH SEX AND
GENDER, AND IT'S SOMETIMES
REALLY HARD TO DISENTANGLE THE
TWO OF THEM.
BUT SO FOR EXAMPLE IN OUR LEWY
BODY DEMENTIA CASES, IN WOMEN
IT'S MUCH MORE COMMON TO HAVE
MULTIPLE PROTEINOPATHY.
SO IT VERY UNUSUAL TO SEE A PURE
LEWY BODY DEMENTIA PRESENTATION.
WOMEN ALSO TEND TO BE A LITTLE
BIT OLDER COMPARED TO MOST MEN.
AND WE'VE DONE A LITTLE BIT OF
RESEARCH ALREADY LOOKING AT SEX
CHROMOSOME DIFFERENCES, AND WE
WERE ABLE TO ACTUALLY SHOW THAT
WOMEN ALSO HAVE THE APOE4 RISK
ALLELE, THEY ARE AT HIGHER RISK
FOR DEVELOPING LEWY BODY
DEMENTIA IF THEY HAVE A CERTAIN
RISK VARYING K PATHWAY WHICH IS
INVOLVED IN LOTS OF DIFFERENT
SIGNALING PATHWAYS THAT HAVE
ALREADY BEEN IMPLICATED IN
ALZHEIMER'S DISEASE, AND WE'RE
STARTING TO JUST SCRAPE THE
SURFACE OF THAT.
WE ALSO ARE SEEING DIFFERENCES
IN THE OVERALL PREVALENCE OF
ALZHEIMER'S DISEASE BEING MUCH
MORE WOMEN-CENTRIC.
LEWY BODY SEEMS TO BE MORE MALE
CENTRIC, MALE-FOCUSED BUT
THERE'S ALSO JUST DIFFERENCES IN
THE WAYS THE DISEASE MAY
MANIFEST.
SO THERE'S A LITTLE BIT WE HAVE
TO BE CAUTIOUS THAT MULTIPLE
CASES HAVE BEEN REPORTED WHERE
WOMEN HAVEN'T BEEN DIAGNOSED
APPROPRIATELY BECAUSE OF THE
CO-PATHOLOGY, THEY MAY NOT QUITE
PRESENT THIS CLASSICALLY AS LEWY
BODY DEMENTIA, SO SOMETIMES IT'S
JUST THE CLINICAL PRESENTATION
MAY NOT ALWAYS BE AT CLEAR-CUT.
SO DEFINITELY THERE'S MORE AND
MORE LITERATURE EMERGING AROUND
DIFFERENCES BUT I THINK WE'VE
JUST STARTED, AT THE MOMENT OUR
TREATMENT APPROACHES ARE PRETTY
MUCH THE SAME FOR MEN AND WOMEN
BUT IT'S A POSSIBILITY THAT SOME
OF THE GENETIC MODIFIERS THAT
WE'RE DEVELOPING MAY BECOME MORE
DEFINED AND MAY REALLY PINPOINT
TO TREATMENTS IN MALES VERSUS
FEMALES.
MAYBE REBECCA, IF YOU WANT TO
ADD SOMETHING FROM THE
EPIDEMIOLOGY SIDE AS WELL.
>> SURE.
THOSE ARE CERTAINLY REALLY
INTERESTING DATA THAT YOU HAVE,
SONJA.
I THINK FROM THE VASCULAR WORLD,
THE TRICKY PART IS THAT WOME%
TEND TO BE TREATED DIFFERENTLY
FOR VASCULAR DISEASE THAN ARE
MEN.
SO STROKE BEING ONE EXAMPLE.
IN GENERAL, WOMEN TEND TO
OUTSURVIVE THEIR SPOUSES SO
GENERALLY, YES, THEY'RE OLDER
WHEN THEY'RE PRESENTING WITH
STROKE, FOR EXAMPLE, THEY'RE
MORE LIKELY TO BE LIVING ALONE
AND TO GET TO THE HOSPITAL
LATER, SO FOR THAT PLUS A
VARIETY OF REASONS, THEY'RE LESS
LIKELY TO GET INTERVENTIONS LIKE
TPA, THROMBECTOMY.
THEY'RE LESS LIKELY TO BE GIVEN
THE SAME SECONDARY PREVENTION
TREATMENTS ACTUALLY, AND THEY'RE
LESS LIKELY TO HAVE SORT OF THE
SAME DEGREE OF REHABILITATION
POST-STROKE THAN MIGHT MEN SO
THAT'S CERTAINLY GOING TO
CONFOUND HOW YOU LOOK AT SEX
DIFFERENCES IN LONG TERM
OUTCOMES INCLUDING COGNITIVE
OUTCOMES.
THERE ARE DATA IN GENERAL THAT
WOMEN TEND TO HAVE HIGHER RATES
OF DEMENTIA, BUT THE DATA ARE A
LITTLE BIT INCONSISTENT WITH
SOME OF THESE OTHER POTENTIAL
MECHANISMS, AND I THINK WE'RE
NOT YET AT THE POINT WHERE WE
COULD SAY ANYTHING ABOUT
DIFFERENCES IN TREATMENT, BUT AS
WE LEARN MORE AND UNDERSTAND THE
IMPORTANCE OF, FOR INSTANCE, HOW
COGNITIVE RESERVE MIGHT BE
DIFFERENT IN MEN VERSUS WOMEN,
THIS IS SOMETHING WE SHOULD
CONTINUE TO THINK ABOUT.
IT'S A GREAT QUESTION.
>> IS THERE ANY ROLE FOR DE NOVO
MUTATIONS AND GENETIC -- IN THE
BRAIN IN THESE NEURODEGENERATIVE
DISORDERS?
>> YEAH, I MEAN, THE STUDIES
LOOKING AT THAT SPECIFICALLY ARE
VERY LIMITED.
BUT THAT'S -- THERE IS A REAL
CONCERN THAT SOME OF THOSE
APPARENTLY SPORADIC CASES COULD
BE DUE TO ACQUIRED MUTATIONS,
MOSAICISM.
I DON'T THINK WE HAVE ALL THE
ANSWERS AS OF YET, BUT IT IS A
POSSIBILITY THAT THAT'S WHAT'S
GOING ON IN SOME OF THOSE
INDIVIDUALS.
>> OKAY.
ONE OF THE OTHER QUESTIONS
THAT'S COME UP IS JUST HEARING
ABOUT THE OVERLAP IN TERMS OF
ETIOLOGIC FACTORS AMONGST THE
DIFFERENT DEMENTIAS.
WHETHER, IN FACT, ONE MIGHT
CONSIDER AT LEAST AT SOME POINT,
NOT QUITE YET BUT AT SOME POINT,
ADOPTING A DIFFERENT TAXONOMY OF
THE DEMENTIAS RATHER THAN USING
TERMS LIKE LEWY BODY AND
FRONTOTEMPORAL AND ALZHEIMER'S
DEMENTIAS THAT MAYBE IT WOULD BE
BETTER TO ORGANIZE THESE IN
TERMS OF GENETIC RISK FACTORS OR
SOME OTHER MOLECULAR
DESIGNATIONS.
>> I THINK THAT'S A GREAT POINT.
THERE IS CERTAINLY DEVELOPMENTS
IN THAT SPACE WHERE WE'RE TRYING
TO USE BIOMARKER-DRIVEN
DIAGNOSTICS.
SO FOR EXAMPLE, JUST VERY
RECENTLY, A NEW BIOMARKER DRIVEN
DIAGNOSTICS HAVE ACTUALLY BEEN
PROPOSED FOR BOTH PARKINSON'S
DISEASE AND LEWY BODY DEMENTIA
COMBINED, THE NEURONAL A
SYNUCLEIN SYSTEM, WHICH HAS ITS
PROS AND CONS BUT IT'S REALLY
GOING KIND OF DOWN THAT ROUTE
OF, YOU KNOW, TRYING TO PINPOINT
WHAT IS THE UNDERLYING
PROTEINOPATHY BASED ON A
BIOMARKER AND THEN TARGET THOSE
PAICIALTS.
IT'S ALREADY BEING SOMEWHAT
SUCCESSFUL IN ALZHEIMER'S
DISEASE, WHERE WE HAVE BEEN
USING BIOMARKERS VERY
SUCCESSFULLY, WE CAN MEASURE
AMYLOID, WE CAN MEASURE TAU IN
CSF BUT NOW WE ALSO HAVE REALLY
GREAT PLASMA BIOMARKERS BECOMING
AVAILABLE AND FOR SYNUCLEIN AS
WELL, IT'S JUST FOR SOME OF THE
PROTEINOPATHIES WE DON'T HAVE
APPROPRIATE BIOMARKERS, WE
CANNOT DISTINGUISH THE DIFFERENT
TAUOPATHIES IN THE LIVING
PATIENT, WE CAN'T REALLY PICK
OUT TDP-43 PATHOLOGY BASED ON
THE BIOMARKER.
THERE'S REAL RESEARCH GOING ON
AND THAT MAY CHANGE BUT AT THE
MOMENT WHAT WE HAVE IS A LOT OF
ANS LANCILLARY TESTS, CLINICAL
SYNDROMES, ET CETERA, AND MAYBE
SOME GENETIC DATA THAT PINPOINTS
CERTAIN FAMILIAL FORMS, AND
THAT'S WHERE WE ARE, BUT IT
COULD CHANGE AS WE REALLY ARE
GETTING BETTER WITH BIOMARKERS.
>> AND I'LL JUST ADD THAT
CERTAINLY IN -- SORRY, GO AHEAD.
>> GO AHEAD, PLEASE.
>>
>> IN THE ALZHEIMER'S WORLD,
CERTAINLY THERE'S BEEN THIS MOVE
TO USING BIOMARKERS AS THE WAY
TO DEFINE WHAT'S HAPPENING, SO
THE ATN FRAMEWORK IS THIS IDEA
WHERE PEOPLE ARE IDENTIFIED BY
AMYLOID TAU AND
NEURODEGENERATION AND PRESENCE
OR ABSENCE AND THESE REPRESENT
SLIGHTLY DIFFERENT THINGS.
THERE'S BEEN A PUSH TO ADD V FOR
VASCULAR TO THAT FRAMEWORK, BUT
AS I POINTED OUT, THERE'S A LOT
OF DIFFERENT FORMS THAT VASCULAR
CONTRIBUTIONS CAN TAKE AND
THAT'S ACTUALLY WHY THERE'S BEEN
A MOVE AWAY FROM THE NAME
VASCULAR DEMENTIA AND MORE TO
THIS CONCEPT OF VASCULAR
CONTRIBUTIONS TO COGNITIVE
IMPAIRMENT AND DEMENTIA BECAUSE
IT'S A CONTRIBUTION BECAUSE OF
SO MUCH MIXED PATHOLOGY.
BUT I THINK YOU'RE ABSOLUTELY
RIGHT, THE OLD TERMINOLOGY IS
DANGEROUS IN SOME WAYS THAT WE
FORGET WE NEED TO THINK ABOUT
THE OVERLAP BETWEEN THESE
PATHOLOGIES.
>> ALL RIGHT.
WELL, THANK YOU.
WE HAVE A QUESTION THAT CAME IN
OVER THE WIRE.
CAN YOU COMMENT ON INFECTIOUS
PROCESSES THAT MIGHT CONTRIBUTE
TO DEMENTIA?
THE RECENT COVID-19 PANDEMIC
COMES TO MIND RIGHT AWAY.
>> SO THERE WERE A COUPLE OF BIG
PAPERS THAT CAME ALONG RECENTLY
SHOWING EVIDENCE OF COGNITIVE
DECLINE IN PEOPLE WHO HAD COVID.
THERE WERE A COUPLE EUROPEAN
STUDIES THAT WERE JUST PUBLISHED
RECENTLY.
ARIC IS PART OF A LARGE
CONSORTIUM OF OTHER COHORTS
CALLED C4R WHICH ARE TRYING TO
COLLECT DATA ON COVID -- FRANKLY
EARLY IN THE PANDEMIC WHEN THIS
EFFORT WAS STARTED, I DON'T
THINK ANYONE HAD A SENSE OF HOW
HIGHLY PREVALENT EXPOSURE TO
COVID AND PO POSITIVITY AT SOME
POINT OVER THE COURSE WERE GOING
TO BE IN THIS POPULATION.
BUT THAT'S GOING TO PROVIDE SOME
DATA DOWN THE ROAD.
WE KNOW IN GENERAL THERE'S
STUDIES THAT SUGGEST POST
INFECTIOUS PEOPLE OF HIGH RISK
OF STROKE AND I'VE ALREADY
MENTIONED THAT THAT'S CERTAINLY
ATTRIBUTED TO SUBSEQUENT RISK
FOR DEMENTIA.
WE KNOW THAT THERE'S EVIDENCE
FOR INCREASED SYSTEMIC
INFLAMMATION.
WHETHER THAT'S DUE TO RECURRENT
INFECTION OR SINGLE ACUTE
INFECTION, WE DON'T UNDERSTAND,
IS ASSOCIATED WITH A LOT OF
THESE COGNITIVE CHANGE MARKERS
AS WELL AS IMAGING MARKERS.
SO CERTAINLY THERE'S A LOT OF
EXCITING WORK IN THIS AREA.
AND THERE ARE LINKS.
IT'S HARD TO STUDY OBVIOUSLY IF
SOMEONE HAS AN INFECTION,
THEY'RE TREATED IN A CERTAIN
WAY, IT'S HARD TO KNOW WHICH
ASPECT OF IT MIGHT BE LEADING TO
RISK IN AN EPIDEMIOLOGIC SETTING
BUT WE'RE GOING TO LEARN A LOT
MORE ABOUT HOW COVID FITS IN,
WHAT LONG COVID LOOKS LIKE, HOW
THAT PATHOLOGY OVERLAPS WITH
THESE OTHER PATHOLOGIES, BUT I
DO WANT TO ADD THAT IF WE'RE
THINKING ABOUT THE EFFECTS OF
THE PANDEMIC RECENTLY, THERE'S
AN ADDITIONAL MAJOR ALTERATION
IN HEALTH WHICH IS SOCIAL
ISOLATION, WHICH RESULTED FROM
IN MANY PEOPLE WHO WERE ISOLATED
BECAUSE OF REDUCING INFECTION
RISK, THAT ALSO WE KNOW IS
ASSOCIATED WITH SOME ADVERSE
BRAIN HEALTH EFFECTS.
SO IT'S REALLY TRICKY TO
SEPARATE OUT THE DIFFERENT
COMPONENTS HERE.
>> FASCINATING TALK.
HAVE YOU LOOKED AT METFORMIN
WITH DEMENTIA?
HAVE YOU TAKEN A LOOK AT THE
ACTION OF METFORMIN?
>> METFORMIN.
WELL, METFORMIN IS A VERY
INTERESTING COMPOUND.
YOU KNOW, IT'S A DIABETES DRUG,
BUT IT'S ALSO A DRUG THAT HAS
BEEN -- AT LEAST THERE'S A GOOD
BODY OF LITERATURE IN ANIMALS SO
IT CAN EXPAND LIFE EXPECTANCY.
SO THERE'S A REALLY INTERESTING
LINK THAT IT COULD HAVE A LOT OF
POSITIVE METABOLIC EFFECTS.
AND SO WE HAVEN'T REALLY STUDIED
IT OURSELVES DIRECTLY WITH
DEMENTIA, BUT I WONDER IF
REBECCA HAS ANY ADDITIONAL DATA
FROM THE EPIDEMIOLOGY FIELD
ABOUT METFORMIN SPECIFICALLY AS
A TREATMENT FOR DEMENTIA.
>> SO BROADLY, CLINICAL TRIALS
LOOKING AT DIABETES TREATMENT
MORE BROADLY SUCH AS ACORMIND
DID NOT SHOW REDUCTION IN
DEMENTIA RATES.
THIS IS CONSISTENT WITH THESE
PATTERNS OF MOST OBSERVATIONAL
DATA -- EVEN THOUGH WE SEE
STRONG RELATIONSHIPS WITH
DIABETES CERTAINLY.
SOME -- I CERTAINLY AM FAMILIAR
WITH SOME STUDIES THAT HAVE
LOOKED AT METFORMIN AND SHOWN
REDUCED ASSOCIATIONS WITH
DEMENTIA.
THREASES A BIG CONCERN ABOUT
CONFOUNDING BY INDICATION, THESE
STUDIES OF PEOPLE ON MEDICATIONS
ARE VERY DIFFERENT FROM PEOPLE
WHO AREN'T.
SO YOU HAVE TO BE -- I HATE TO
SOUND LIKE A SKEPTIC ABOUT
EVERYTHING THAT'S NOT SORT OF
CLEARLY ADJUSTED AND IT'S
CONFOUNDING AS AN ADDRESS BUT
IT'S NOT CLEAR TO ME THAT
EVIDENCE ARE CLEARLY POINTING TO
MEMETFORMIN IN REDUCING DEMENTIA
RISK BUT I SUSPECT THIS IS ALSO
AN EXAMPLE WHERE IT MAY BE A
LONGER EFFECT AND CERTAINLY
DOING IN A SHORT PERIOD OF TIME
MAY NOT BE ENOUGH TO ACTUALLY
SHOW A CHANGE IN COGNITIVE
OUTCOMES.
BUT THAT'S AN EXAMPLE WHERE
UNDERSTANDING THE MECHANISTIC
LINKS IN IMAGING MAY GIVE US A
SURROGATE END POINT THAT WE CAN
USE TO UNDERSTAND IF THERE'S A
POSSIBILITY OF POTENTIAL
INTERVENTIONS FOR LONGER TERM
OUTCOMES.
>> WELL, THANK YOU.
SO WE HAVE SEVERAL QUESTIONS
THAT HAVE COME IN OVER THE WIRE.
WHAT COULD BE THE NEXT STUDIES
DONE TO TARGET MISSING
UNDERSTANDING BETWEEN COGNITIVE
DECLINE AND MID LIFE LIFESTYLES?
SO I THINK I'M GOING TO BUILD ON
THAT LAST COMMENT THAT I MADE
WHICH IS THAT WE ARE NOT -- I
DON'T THINK ANYONE IS EVER GOING
TO DO THE TRIAL THAT IS LEADING
TO INTERVENTIONS IN MID LIFE
VASCULAR RISK FACTORS AND
FOLLOWS THEM FOR 30 YEARS
BECAUSE THAT'S NOT PRACTICAL.
I THINK THE KEY IS FINDING
BIOMARKERS THAT ARE REASONABLE
SURROGATE END POINTS AND THERE
IS A STUDY CALLED MARK VCID
WHICH IS AN STRAL MURAL
NINDS-FUNDED STUDY WHICH IS
TRYING TO DO EXACTLY THAT.
IDENTIFY BIOMARKERS FOR VASCULAR
CONTRIBUTIONS TO DEMENTIA SO
THAT POTENTIALLY AMONG OTHER
THINGS, THEY COULD BE PLUGGED
INTO A TRIAL SETTING SO THAT
INTERVENTIONS COULD HAPPEN IN
MID LIFE AND IF WE SEE A
SURROGATE END POINT THAT'S
MODIFIED, THAT MIGHT ACTUALLY
POINT TO THAT AS BEING A
VALUABLE INTERVENTION LONGER
TERM.
I THINK THE OTHER CONSIDERATION
IS -- SO IN THE ALZHEIMER'S
COMMUNITY IN GENERAL, TRIALS
DON'T ENROLL PEOPLE WITH
VASCULAR DISEASE BECAUSE THEY
WANT TO SEE THE PURE EFFECT OF
POTENTIAL TREATMENT.
I UNDERSTAND THAT, IN LEWY BODY
DEMENTIA, I SUSPECT THAT YOU
DON'T WANT TO ENROLL PEOPLE WHO
HAVE A LOT OF MIXED PATHOLOGY AS
A SORT OF PROOF OF CONCEPT.
IN THE VASCULAR WORLDS, WE DON'T
NECESSARILY PAY ATTENTION TO THE
OTHER PATHOLOGIES EITHER AND I
THINK THE MORE WE UNDERSTAND
ABOUT WHO WE'RE RECRUITING INTO
STUDIES, THE MORE WE'LL
UNDERSTAND WHY WE MIGHT SEE AN
EFFECT OR WHY WE DON'T.
SO I THINK THINKING ABOUT THESE
MIXED POPULATIONS COULD BE
EXCITING, THINKING ABOUT
MULTIMODAL INTERVENTIONS THAT
EVEN EXTEND TO AD-SPECIFIC
TREATMENTS AS WE START TO
DEVELOP THOSE COULD BE PRETTY
EXCITING.
BUT I THINK FOR THE TIME BEING,
FINDING WHAT'S A GOOD SURROGATE
END POINT THAT WE'RE WILLING TO
TRUST WE THINK ACTUALLY
REPRESENTS AN IMPORTANT PATHWAY
ON HOW THESE RISK FACTORS MIGHT
BRING LATER LIFE BRAIN HEALTH.
GENOMICS MIGHT -- IN SORT OF
DETERMINING WHO ARE THE PEOPLE
AT HIGHEST RISK WHO WE SHOULD
STUDY.
>> IDEALLY WE WANT TO HAVE A
ELECTRONIC HEALTHCARE DATABASE
FROM BIRTH ALL THE WAY UP TO
DEATH, SO NOT JUST -- WE HAD
MEDICARE WHICH STARTS AT 65 SO
IDEALLY YOU MAY HAVE TO GO TO
OTHER COUNTRIES, EUROPEAN
COUNTRIES WHERE THEY REALLY HAVE
KIND OF A SOCIALIZED KIND OF
HEALTHCARE SYSTEM WHERE WE CAN
LOOK AT THESE RISK FACTORS ON A
LONGITUDAL SCALE.
SO EPIDEMIOLOGICAL STUDIES ARE
STILL VERY RELEVANT IN THIS
CONTEXT BUT IT'S HARD TO PIECE
THE CIRCUMSTANTIAL EVIDENCE ALL
TOGETHER BECAUSE NOT EVERYBODY
WILL BE ABLE TO DO ALL THESE
LONG TERM CLINICAL TRIALS OVER
DECADES BUT EVIDENCE THAT'S
EMERGING IS STILL QUITE
COMPELLING THAT IT'S REALLY
IMPORTANT TO TAKE CARE OF YOUR
VASCULAR HEALTH, BE ACTIVE AND
HEALTHY.
ALL THE THINGS WE WERE TOLD BY
OUR MOTHERS.
>> ANOTHER THING I GUESS WE'VE
BEEN TOLD BY OUR MOTHERS AND
PERHAPS JUST TO OBSERVE THROUGH
LIFE IS THE QUESTION OF THE ROLE
OF SLEEP IN THE DEVELOPMENT OF
COGNITIVE IMPAIRMENT.
ARE THERE ANY DATA WITH REGARD
TO AVERAGE AMOUNTS OF SLEEP OR
OCCUPATIONS THAT LEAD TO SLEEP
DEPRIVATION AND RISK OF
COGNITIVE DECLINE OR DEMENTIA?
>> WE BOTH HAVE SOMETHING TO SAY
ABOUT THIS.
DO YOU WANT TO TALK ABOUT IN THE
CONTEXT -- I HAVE A LOT TO SAY.
>> I'LL LEAVE THE -- BUT YES,
SLEEP DISRUPTION IS A VERY
COMMON FEATURE OF MOST
NEURODEGENERATIVE DISEASES, AND
YOU KNOW, IT IS AN IMPORTANT
THING THAT WE REALLY ADDRESS IN
THE CLINIC, PAYING ATTENTION TO
SLEEP DYSFUNCTION AND TRYING TO
REALLY TREAT THE PATIENTS, AND
REALLY COUNSEL PATIENTS ABOUT
SLEEP HYGIENE.
BECAUSE IF YOU DO NOT SLEEP
WELL, YOU CANNOT THINK WELL.
SO NOBODY DOES THAT.
SO IT'S A CRUCIAL METABOLIC
STATE THAT WE REALLY NEED TO BE
ABLE TO TEACH OUR PATIENTS WHAT
IS GOOD SLEEP HYGIENE.
BUT THEN THE QUESTION ALSO IS
WHAT IS CHICKEN VERSUS EGG.
I MEAN, IN SOME INSTANCES, IF
YOU HAVE A LOT OF SLEEP
DISRUPTION, INDEPENDENTLY TO
WHICH DOES THAT DRIVE THE
UNDERLYING DISEASE PATHOGENESIS.
SO MAYBE THE EPIDEMIOLOGY CAN
GIVE YOU A FEW MORE QUEUES, SO
REBECCA, WHAT DO YOU THINK?
>> SO THIS WAS NOT A PLANT BUT
I'LL POINT OUT THAT I WAS THE
LEAD AUTHOR ON A SCIENTIFIC
STATEMENT FROM THE AMERICAN
HEART ASSOCIATION JUST PUBLISHED
IN JANUARY ON SLEEP AND SLEEP
DISORDER AND BROAT BREATHING ANN
HEALTH WHERE A GROUP OF EXPERTS
REALLY SORT OF DESCRIBES BOTH
THE ANIMAL DATA POINTING TO THE
IMPORTANCE OF SLEEP QUALITY AND
QUANTITY AND THE DANGER OF SLEEP
DISORDER AND BREATHING ON BRAIN
HEALTH.
SO THERE'S EVIDENCE FROM
EPIDEMIOLOGIC DATA THAT TOO
LITTLE SLEEP IS ASSOCIATED WITH
A HIGHER RISK OF DEMENTIA, BUT
THIS LAST POINT AND ALSO THAT
SLEEP DISORDERED BREATHING IS
ASSOCIATED WITH A HIGHER RISK OF
DEMENTIA.
THE BIGGEST ISSUE IS THIS
CHICKEN OF EGG, THIS IDEA OF
REVERSE CAUSATION, WHICH IS THAT
WE KNOW THAT DEMENTIA ITSELF CAN
LEAD TO ALTERATIONS IN SLEEP.
WE KNOW THERE'S EVIDENCE FOR AN
ASSOCIATION BETWEEN SLEEP
DISTURBANCES AND SUBSEQUENT
COGNITIVE DECLINE.
IN THE ARIC COHORT, WE ACTUALLY
HAVE A SUBSTUDY WHICH I LED WHEN
I WAS AT HOPKINS CALLED THE ARIC
PET SLEEP STUDY, THEY HAVE MID
LIFE POLYSOMOGRAPHY AS WELL AS
SLEEP QUESTIONNAIRES SO THAT
WE'RE ACTUALLY ABLE TO SEPARATE
IN TIME THE SLEEP DISTURBANCES
AS WELL AS LATER LIFE BRAIN
AMYLOID AND INCIDENT DEMENTIA.
SO SLEEP IS THE NEW LIFE -- WHAT
WAS LIFE SIMPLE 7 AND IS NOW
LIFE ESSENTIAL 8, THE EIGHTH
COMPONENT IS SLEEP IS THAT THE
AMERICAN HEART ASSOCIATION
ADDED.
SO IT'S UNDOUBTEDLY IMPORTANT,
IT'S IMPORTANT FOR STROKE RISK.
WE KNOW THAT AFTER STROKE, SLEEP
DISTURBANCES CAN LEAD TO WORSE
RECOVERY AS WELL AS SORT OF
WORSE REHAB POTENTIAL, SO IT'S
INCREDIBLY IMPORTANT AND IT
APPEARS TO BE SOMEWHAT
INDEPENDENT OF THESE VASCULAR
RISK FACTORS.
THE OTHER REALLY IMPORTANT WAY
THAT SLEEP IS IMPORTANT IS
THROUGH THIS IDEA OF THE
LYMPHATIC SYSTEM.
SO I MENTIONED EARLY ON WHEN I
WAS DISCUSSING POSSIBLE BIOLOGIC
MECHANISMS THAT THE LYMPHATIC
SYSTEM HAS THIS GENERAL CONCEPT
OF CLEARING TOXINS FROM THE
BRAIN SUCH AS AMYLOID BETA, AND
WE THINK THAT THAT HAPPENS
DURING SLOW WAVE SLEEP WHICH IS
ONE OF THE STAGES OF SLEEP AND
IN GENERAL, IF YOU HAVE ANYTHING
THAT LEADS TO LESS EFFICIENT OR
LESS SLOW WAVE SLEEP IT'S
POSSIBLE YOUR LYMPHATIC FUNCTION
WILL BE WORSE, THUS LEADING TO
POTENTIAL BUILDUP OF THESE
PROTEINS.
SO THANK YOU FOR ASKING ABOUT
SLEEP.
I DO WANT TO SAY, I THINK WIN IS
TRYING TO ASK A QUESTION ON ZOOM
AND I DON'T KNOW IF THAT'S -- I
JUST WANT TO MAKE SURE THAT --
>> YES, LET'S HAVE WIN POSE HIS
QUESTION.
WIN?
>> SO MANY YEARS AGO, THE TOWN
OF FRAMINGHAM WAS SUBJECT TO
TOTAL DATA RECALL, AND THAT WAS
FOLLOWED UP UNTIL THE LAST I
HEARD MAYBE ABOUT 15 YEARS AGO.
SO QUESTION.
DATA FROM THE FRAMINGHAM STUDY
ACTUALLY WELL DONE AND OVER A
PERIOD OF TIME, ARE THEY
ACCESSIBLE AND ARE THEY
VALUABLE, AND AS A SUBSET TO
THAT, ONE READS ABOUT THE
RELATIONSHIP BETWEEN ZIP CODES
AND VARIOUS DEGENERATIVE
DISEASES OF METABOLISM, ET
CETERA, ET CETERA.
IS THERE A RELATIONSHIP TWEENL
ZIP CODES AND DEMENTIA?
>> SO I THINK I'LL TA TAKE A FIT
STAB AT THAT.
CERTAINLY THE FRAMINGHAM DATA
ARE WONDERFUL.
WE HAVE A LOT OF CONSORTIA WHERE
WE PULL DATA BETWEEN ARIC AND
FRAMINGHAM.
FRAMINGHAM IS NOT AN INCREDIBLY
DIVERSE COHORT AND THAT'S REALLY
IN MY OPINION THE MAJOR
POTENTIAL WEAKNESS.
BUT WE'VE LEARNED A TREMENDOUS
AMOUNT AND WE CONTINUE TO DO SO
FROM THE FRAMINGHAM STUDY.
AND THERE ARE FRIENDS THAT ARE
HEAVILY INVOLVED IN IT, THE DATA
ARE REALLY VALUABLE, BUT I
ACTUALLY THINK YOUR SECOND
QUESTION HIGHLY RELATES TO THAT
ISSUE.
SO FRAMINGHAM IS A VALUABLE
STUDY IN A NOT DIVERSE COHORT IN
ONE ZIP CODE BASICALLY OR IN ONE
PART OF THE WORLD.
SO AMY KIND AT UNIVERSITY OF
WISCONSIN DEVELOPED SOMETHING
CALLED THE AREA DEPRIVATION
INDEX, WHICH IS A WAY TO USE
YOUR -- WHERE YOU LIVE,
BASICALLY YOUR ZIP CODE, TO
DETERMINE THE LEVEL OF
NEIGHBORHOOD DEPRIVATION BASED
ON SOCIOECONOMIC STATUS OF
PEOPLE THAT LIVE THERE, WHAT'S
AVAILABLE TO THE COMMUNITY, ET
CETERA.
THERE'S PRETTY GOOD COMPELLING
EVIDENCE THAT ADI, THIS AREA
DEPRIVATION INDEX, IS ASSOCIATED
WITH BRAIN HEALTH INCLUDING
DEMENTIA AND COGNITIVE DECLINE,
SO CERTAINLY THERE'S A LOT OF
FACTORS AT PLAY.
WE KNOW THAT EDUCATION TENDS TO
BE LOWER IN AREAS WITH A WORSE
AREA DEPRIVATION INDEX.
IS IT BECAUSE OF EDUCATION, IS
IT BECAUSE OF FINANCIAL ASPECTS.
WE'RE TRYING TO UNDERSTAND HOW
MUCH DISPARITIES THAT WE SEE IN
THIS COUNTRY IN DEMENTIA RATES
AND IN STROKE RATES AS WELL, HOW
MUCH OF THAT IS EXPLAINED BY
THESE NEIGHBORHOOD LEVEL FACTORS
WHICH WE KNOW ALTER IN
COMBINATION WITH THINGS LIKE IN
GENESIS STE MIBG RACISM WE'RE
GOING TO ALTER ACCESS TO
HEALTHCARE AND LIKELIHOOD OF
GETTING YOUR RISK FACTORS AS
WELL CONTROLLED, ET CETERA,
WHICH IN TURN CAN AFFECT BIOL
BIOLOGY.
SO CERTAINLY THINKING ABOUT
WHERE PEOPLE COME FROM AND WHERE
THEY LIVE IS, I THINK, A REALLY
IMPORTANT WAY WHEN WE THINK
ABOUT THIS OTHER ASPECT OF
COGNITIVE RESERVE AND SOCIAL
FACTORS AND HOW THEY MAY
INTERPLAY AND HOW WE CAN
POTENTIALLY REDUCE RISK OF
DEMENTIA NOT JUST BY ACTING ON
GENETIC FACTORS AND BIOLOGIC
FACTORS, BUT ALSO SOME OF THESE
SOCIAL FACTORS AS WELL.
SO THANKS FOR ASKING ABOUT
THOSE.
>> WELL, WE'RE GETTING CLOSE TO
THE END, BUT MAYBE JUST THINKING
A LITTLE BIT IN TERMS OF THE
NETHER ZONE BETWEEN NORMAL
EXPERIENCE AND DEMENTIA,
QUESTION COMES UP OF FO FORGETTG
NAMES AND THE FACT THAT THAT'S
SOMETHING THAT SEEMS TO HAPPEN
AS LIFE PROGRESSES.
IS THERE ANY REASON WHY THAT IN
PARTICULAR IS AN AREA OF LOSS,
OR IS IT JUST THAT THAT'S
EMBARRASSING AND SO IT NOTICED
FIRST?
>> I THINK IT'S CERTAINLY TO
SOME EXTENT BECAUSE IT'S A
NOTABLE IMPAIRMENT.
WHEN WE LOOK AT COGNITIVE
PERFORMANCE OVER THE LIFESPAN,
WE DO SEE, YOU KNOW, SLIGHT
DROPS IN MULTIPLE DOMAINS.
BUT IN GENERAL, WHILE NAMING IS
SOMETHING THAT MANY PEOPLE
EXPERIENCE, IN GENERAL IT IS
SOMETHING THAT CAN BE PRESERVED
VERY LATE IN LIFESPAN.
SO LANGUAGE ABILITY, YOU'RE
STILL ABLE TO BUILD THAT, AND I
THINK IT JUST HIGHLIGHTS THE
EVOLUTIONARY IMPORTANCE OF
LANGUAGE FUNCTION, SO IF YOU
EXPERIENCE MILD DIFFICULTY, UR
MAY JUST FEEL MORE IMPAIRED
BECAUSE SOCIALLY WE ARE SO
DEPENDENT ON THIS PARTICULAR
DOMAIN.
BUT A LITTLE BIT OF LOSS IS PART
OF THE NORMAL AIMING PROCESS. A.
>> DR. GOTTESMAN, DO YOU HAVE
ANYTHING TO ADD TO THAT?
>> SONJA, I NOTICED THAT YOU
MENTIONED EARLY ON THAT OFTEN A
PRESENTING SYMPTOM OF
ALZHEIMER'S DISEASE WAS
FORGETTING NAMES AND I WAS
WORRIED HOW MANY PEOPLE WERE
PANICKING THAT YOU JUST -- SO WE
KNOW WITH AGING, IT IS
INCREDIBLY COMMON AND IT ONE OF
THE MOST COMMON COMPLAINTS THAT
PEOPLE HAVE WHO DO NOT GO ON TO
PROGRESS TO ANY OF THESE
DISORDERS.
BUT I DON'T -- I MEAN, I THINK
IT'S A GREAT QUESTION, WHAT IS
IT ABOUT THE STRUCTURE OF THE
BRAIN AND WHAT HAPPENS WITH AGE
AS TO WHY NAMING IS AFFECTED
BECAUSE AS SONJA POINTS OUT,
IT'S NOT AFFECTED -- LANGUAGE IS
NOT USUALLY AFFECTED SO EARLY IN
THESE OTHER CONDITIONS.
BUT I DON'T THINK WE KNOW MORE
AS TO WHY SPECIFICALLY, AND I
THINK THAT PROPOSED IDEA OF IT'S
JUST MORE NOTICEABLE MAKES AS
MUCH SENSE AS ANY OTHER
EXPLANATION THAT WE HAVE.
>> ALL RIGHT.
WELL, I THINK THAT, YOU KNOW,
ALL GOOD THINGS MUST COME TO AN
END, AND THIS IS ANOTHER EXAMPLE
OF THAT.
JUST TO REPEAT THE CME CODE FOR
THOSE WHO WANT TO GET CONTINUING
MEDICAL EDUCATION CREDIT, IT IS
52095.
AND I THINK THAT AT THIS POINT,
WE WILL HAVE TO CALL THINGS TO A
CLOSE.
THANK THE SPEAKERS VERY, VERY
MUCH FOR A WONDERFUL
PRESENTATIONS AND WONDERFUL
DISCUSSION AFTERWARDS, AND WE
LOOK FORWARD TO THE NEXT SESSION
OF DEMYSTIFYING MEDICINE, WHICH
IF YOU CAN BELIEVE IT IS GOING
TO BE OVER IN LIPSETT AUDITORIU.
AND WE'RE GOING TO BE OVER THERE
FOR THE SECOND HALF OF THE
SEASON.
DR. ARIAS AND I HAVE A BET GOING
AS TO HOW MANY PEOPLE ARE GOING
TO SHOW UP AT LIPSETT AS OPPOSED
TO BUILDING 50.
AND I WON'T TELL YOU WHO'S
BETTING ON WHAT.
BUT ANYWAY, I HOPE TO SEE ALL OF
YOU OVER IN LIPSETT NEXT
TUESDAY, AND WITH THAT, THANK
YOU AGAIN TO OUR SPEAKERS AND TO
ALL OF OUR PARTICIPANTS, AND A
GOOD EVENING TO EVERYONE.
>> BRAVO!