TODAY WE WILL BE HEARING
SOMETHING DIFFERENT, WHICH I
THINK IS VERY BENEFICIAL FOR US
[INDISCERNIBLE] PROT PROTEOMI,
AND ALSO TECHNOLOGY DEVELOPMENT
SO TODAY IT'S A GREAT FACTOR TO
HAVE 1 OF OUR OWN NIH
INVESTIGATORS HERE TO GIVE US A
TALK DR. KEENAN WALKER IS A
TENURED TRACK INVESTIGATOR AT
THE NATIONAL INSTITUTE ON AGING
IN THE INTRAMURAL PROGRAM.
HE RECEIVED HIS Ph.D. HAD
CLINICAL PSYCHOLOGY FROM
ST. JOHNS UNIVERSITY AND THEN
DID HIS PREDOCTORAL INTERNSHIP
AT THE UNIVERSITY OF CALIFORNIA
SAN DIEGO IN THE HEALTHCARE
SYSTEM.
AFTER THAT HE DID A NIH FUNDED
POST DOC AT JOHNS HOPKINS
UNIVERSITY SCHOOL OF MEDICINE IN
AGE RELATED COGNITIVE DISORDERS.
I GUESS THAT'S WHAT BROUGHT YOU
TO OUR AREA.
HE LATER TRANSITIONED TO
ASSISTANT PROFESSOR OF NEUROLOGY
AFTER RECEIVING A K3 CAREER
DEVELOPMENT AWARD.
AND THEN SHORTLY AFTER THAT HE
BEGAN AS A TENURED TRACKER AT
NIA.
CURRENTLY DR. WALKER IS A
[INDISCERNIBLE] OF THE
MULTIMODAL IMAGES OF
NEURODEGENERATIVE DISEASE, AND
THE LABORATORY OF BEHAVIORIAL
NEUROSCIENCE, HIS RESEARCH
FOCUSES ON THE ROLE OF
UNDERSTANDING NORMAL IMMUNE
FUNCTION AND INFLAMMATION IN
[INDISCERNIBLE] DISEASE AND LATE
[INDISCERNIBLE] COGNITIVE
DECLINE.
SO WITHOUT FURTHER ADO HERE IS
DR. WALKER.
>> WELL, THANK YOU, THANK YOU
FOR THE INVITATION, APPRECIATE
THE INTRODUCTION, SO, YEAH, IT'S
A SMALL GROUP SO WE'LL KEEP IT
INFORMAL IF IMK HAS ANY
QUESTIONS, FEEL FREE TO TOP AND
ASK, HOPEFULLY THAT'S OKAY WITH
THE VIDEOCAST SO WE WILL GO
AHEAD AND GET STARTED.
LIKE WAS SAID, I WAS TRAINED AS
A CLINICAL NEUROPSYCHOLOGIST,
ALTHOUGH, WHY AM I DOING
PROTEOMIC, MAKE IT GOES TO SHOW
HOW DEMOCRATIZES PROTEOMICS HAS
GOTTEN WITH THE ADVENT OF SOME
OF THESE LARGE SCALE PLATFORMS
LIKE THE 1S I WILL TALK ABOUT
TODAY, I CLEARLY HAVE MADE A
PRETTY STARK TRANSITION FROM MY
AREA OF THE PAINTING BUT I THINK
HOPEFULLY IT BECOMES CLEAR WHY
WE PLANNED ON USING PROTEOMICS
AS A TOOL, UNDERSTANDING MORE
ABOUT DEMENTIA SO SOME
DISCLOSURES, YOU DON'T NEED
THOSE, SO, I KNOW EVERYONE
STUDIES SOMETHING DIFFERENT IN
TERMS OF DISEASES HERE, SO I
THOUGHT WE WOULD JUST START BY
TALKING ABOUT WHAT I STUDY JUST
SO WE'RE ALLOT SAME PLAYING
FIELD, SO ALZHEIMER'S DISEASE IS
JUST 1 FORM OF DEMENTIA, THERE
ARE MANY FORMS OF DEMENTIA, IT
REPRESENTS TWIN STUDIES THIRDS
OF ALL DEMENTIA CASES.
SO YOU KNOW YOU CAN--ABOUT,
WELL, OVER 10% OF PEOPLE OVER 65
RIGHT NOW ALZHEIMER'S DISEASE,
DEMENTIA AND THIS IS ONLY GOING
TO INCREASE WITH TIME ESPECIALLY
AS THE POPULATION AGES, SO WHAT
DO WE MEAN WHEN I SAY
ALZHEIMER'S DISEASE OR DEMENTIA?
WELL, REALLY BIOLOGICALLY IT'S
THE BY AND BY AMYLOID AGGREGATES
THAT OCCUR OUTSIDE THE CELL AND
THESE TAU TANGLES THAT HAPPEN
INSIDE THE CELL AND BEYOND THAT,
THERE ARE A NUMBER OF OTHER
PROCESSES THAT OCCUR INCLUDING
MICROGLIAL ACTIVATION WHICH
SPARKS NEURAL INFLAMMATION
SPECIFICALLY.
SO MY HYPOTHESIS AND THIS IS
WITH THE A LOT OF WORK WE DO IS
THAT CONDITIONS OUTSIDE THE
CENTRAL NERVOUS SYSTEM CAN
INFLUENCE DEMENTIA RISK, THIS
HAS BEEN UPDATED BUT THE YOU
KNOW THE POINT I WANT TO DRIVE
HOME IS ANYWHERE FROM 30-40% OF
THE ATTRIBUTABLE RISK FOR
DEMENTIA IS DUE TO CONDITIONS
THAT LARGELY LIE OUTSIDE THE
CENTRAL NERVOUS SYSTEM, SO THESE
ARE CONDITIONS THAT ARE LARGELY
MODIFIABLE TO EXTENT IN AITION
TO WHATEVER BENEFITS CAN OCCUR
THROUGH, YOU KNOW CNS DIRECTED
THERAPY.
AND YOU KNOW IT'S OUR BELIEF
THAT PROTEINS IN CIRCULATION,
PROTEINS IN BLOOD MIGHT MEDIATE
THE RELATIONSHIPS BETWEEN
CONDITIONS LIKE CARDIO METABOLIC
DISEASE, AUTOIMMUNE CONDITION,
YOU KNOW AND THESE RISK FACTORS
FOR DEMENTIA THAT ESSENTIALLY
WILL INCREASE ONCE DEVELOPING
DEMENTIA ACROSS THEIR LIFETIME
AND HOW DOES THAT WORK, WELL, WE
THINK THAT WHEN YOU DO HAVE A
CLINICAL DISEASE, OR THIS COULD
BE CLINICAL CONDITIONS THAT
AREN'T DIAGNOSED OR NOTABLE OR
CLINICAL PROCESSES LIKE CELLULAR
AGING BUT ALL THESE CONDITIONS
PART OF WHAT THEY DO IS THEY
CHANGE THE EXPRESSION OF
PROTEINS ACROSS DIFFERENT ORGAN
SYSTEMS, ACROSS DEFINITE CELL
TYPES AND THESE ALL FILTER INTO
THE BLOOD OF SOME MORE THAN
OTHERS, BUT THE IDEA IS THAT
WHEN THEY MAKE IT INTO THE BLOOD
STREAM THEY CAN ACROSS INTO THE
CENTRAL NERVOUS SYSTEM THROUGH
VARIOUS CONDUITS SO I WILL TALK
ABOUT THESE MORE LATER, BUT
THESE PROTEINS WE THINK
INFLUENCE SOME OF THE TARGET
CELLS WITHIN THE BRAIN ASK
INFLUENCE BEHAVIOR, YOU KNOW
DRIVE, DISEASE, ET CETERA.
SO A NUMBER OF THESE PROTEINS
HAVE BEEN IDENTIFIED.
A LOT OF THEM AS YOU SEE HERE
ARE CYTOKINES AND CHEMOKINES,
THEY INCREASE WITH AGE OR
DECREASE WITH AGE AND THEY HAVE
SOME KNOWN EFFECT ON TARGET
CELLS WITHIN THE BRAIN.
WE THINK THERE'S MANY, MANY MORE
PROTEINS OUT THERE INVOLVING
[INDISCERNIBLE] THAT POTENTIALLY
MIGHT BE USED AS BIOMARKERS BUT
ALSO THERAPEUTIC TARGETS.
SO WE GOT INTO THIS THE STUDIES
SOMA
SCAN INTRODUCED THEIR PRODUCT.
SO FOR THOSE THAT DON'T KNOW,
SOMA SCAN IS A LARGE COMPANY
THAT WILL ALLOW YOU TO MEASURE
THINGS AND SO I WAS WORKING WITH
A LARGE COHORT THAT ALLOWED US
TO IMPLEMENT THE SOMA SCAN OF
THIS LARGE GROUP OF PROTEOMICS
AND WITH THAT, BEFORE THIS I WAS
REALLY INTERESTED IN SYSTEMIC
INFLAMMATION AS A FACTOR,
PROTEINS, IL6, PROTEINS THAT
HAPPEN TO BE MEASURED IN A
COHORT AND RELATING THEM TO
NEUROCOGNITIVE OUTCOME, WE WERE
LOOKING AT 1 PROTEIN AT A TIME,
WE WERE USING PROTEINS AGAIN OF
CONVENIENCE AND WE WERE COMING
TO CONCLUSIONS BASED ON A REALLY
BIASED SELECTION OF POTENTIAL
PROTEIN TARGETS, SO, YOU KNOW I
WAS REALLY EXCITED WHEN WE HAD
THIS UNBELIEVABLE OPPORTUNITY TO
LOOK AT THOUSANDS OF PROTEINS,
YOU KNOW MY INTEREST IN THE'MUNE
DYSFUNCTION SPECIFICALLY, AND
THERE WERE HUNDREDS OF PROTEINS,
HUNDREDS OF IMMUNE PROTEINS ON
THIS PANEL ALREADY, SO I WAS
LIKE, OKAY, LET'S DO THIS AND WE
WENT AND WE STARTED LOOKING AT
THE SIGNATURE OF VARIOUS CENTRAL
NERVOUS SYSTEM RELATED
CONDITIONS AND THERE WAS A LOT
OF, YOU KNOW SKEPTICISM
INITIALLY ABOUT WHETHER OR NOT
LOOKING AT BLOOD, PROTEOMICS WAS
GOING TO GIVE US ANY INFORMATION
ABOUT A CENTRAL NERVOUS SYSTEM
CONDITION AND BLOOD BRAIN
BARRIER, ET CETERA, WE DON'T
REALLY THINK OF DEMENTIA AS
BEING DRIVER BY STUFF IN THE
BLOOD STREAM BUT THERE'S BEEN A
LOT OF EVIDENCE TO SUPPORT THAT,
AT LEAST TO SOME EXTENT THAT IT
CAN BE, SO OUR FIRST PAPER WAS
PUBLISHED IN 2021 IN NATURE
ANDIGING WHICH LOOKED AT THESE
5000 PROTEINS MEASURED BY THE
SOMA SCAN PLATFORM AND RELATED
THEM ACROSS A 5 YEAR FOLLOW UP
PERIOD.
SO WHAT WE FOUND WAS A NUMBER OF
PROTEINS THAT WERE LINKED TO
DEMENTIA WHICH WE CAN SAY MIGHT
BE USED AS BIOMARKERS, WE WENT
FURTHER AND DID CAUSAL INFERENCE
USING MEN DEALIAN RANDOMIZATION,
WE WERE ABLE TO IDIDN'TIFY
POTENTIAL MECHANISTICALLY
RELEVANT PROTEINS WHICH WE THINK
MIGHT BE VIABLE DRUG TARGETS.
NOW IN THIS PAPER WE WERE
LOOKING IN OLDER ADULTS, AND
THERE WAS A STRING OF PAPER
USING O-LINK, USING SOMA
KAN--KANA, USING MASS SPEC. THAT
LOOKED AT THE PROTEOME IN BLOOD
FOR FUTURE PREVALENT DEMENTIA
BUT WE RECOGNIZE THAT DEMENTIA
STARTS WELL, WELL BEFORE LATE
LIFE.
ALZHEIMER'S DISEASE, 1 FORM OF
DEMENTIA STARTS DECADES BEFORE
DEMENTIA ONSET SO YOU HAVE THIS
PRECLINICAL PERIOD HERE WHICH
OCCURS FOR YEARS BEFORE PEOPLE
EXPRESS SYMPTOMS, NOW MILD
COGNITIVE IMPAIRMENT IS THIS
DEMENTIA [INDISCERNIBLE] AND
THEN THIS CAN LAST FOR DECADES
SO THE CONSENSUS IS THAT
ALZHEIMER'S DISEASE WITH THE
PATHOGENESIS STARTS IN MIDLIFE
OR MITSD ADULTHOOD SO WE
THOUGHT, OKAY, IF WE'RE REALLY
GOING TO UNDERSTAND THE DISEASE
BIOLOGY USING A PROTEOMIC LENS
WE NEED TO ELECTRIC IN MIDDLE
AGED ADULTS, SO THAT'S WHAT WE
DID, WE WENT BACK TO THE SAME
COHORT THAT WE DID OUR INITIAL
STUDY IN AND MEASURE PROTEOME IN
BLOOD 20 YEARS EARLIER THAT HAD
BEEN BANKED AND WAS AVAILABLE
AND SO THE COHORT THAT WE WORK
WITH WAS THE ERIC STUDY, SO ERIC
IS THE ABNORMAL GLUCOSE
TOLERANCELER O CLEROSEIS RISK IN
COMMUNITY STUDY AND THIS A
MULTISITE COMMUNITY BASED COHORT
THAT'S STILL ACTUALLY ONGOING
BUT IT'S A STUDY THAT'S DRAWN
ACROSS 4 UNITED STATES
COMMUNITIES AND INITIALLY
ENROLLED 16,000 INDIVIDUALS IN
THE LATE 80S, SO THESE CONTINUED
TO BE FOLLOWED AND WHAT WE WERE
LUCKY ENOUGH TO DO IS TAKE BLOOD
FROM THE THIRD VISIT WHICH
OCCURRED IN 93 AND RELATE,
MEASURE THE PROTEOME AGAIN WITH
THIS 5000 SOMA SCAN PLATFORM AND
RELATE THOSE TO 1 BY 1 TO
SUBSIDIARY QUEBT OR FUTURE
DEMENTIA REG, AND WE LOOK ACROSS
THE FOLLOW UP TIME OF 25 YEARS
IN THE STUDY, WE LOOKED ACROSS A
SHORTER TERM, 15 YEARS AND THEN
BEYOND 15 YEARS TO SEE HOW
PROTEINS HAVE CHANGED.
THIS IS FROM OUR FULL ANALYSIS
AND THIS IS WITH ADJUSTMENT FOR
CO VALID AND RELIABLEIATES,
REALLY TRYING TO UNDERSTAND WHAT
MECHANISTICALLY RELEVANT,
THEY'RE NOT SIMPLY BIOMARKERS
BUT YOU CAN SEE GD15 RISING WELL
ABOVE THE REST AND THEN A NUMBER
OF OTHER ABOUT 30 PROTEINS THAT
PASS THE [INDISCERNIBLE] FOR ANY
CORRECTED LEVEL OF STATISTICAL
SIGNIFICANCE, SO WE TOOK A
DEEPER DIVE INTO THIS SET OF
PROTEIN ANDS THIS IS THE SET
FROM THE FULL FOLLOW UP, WE DID
FOLLOW UP WITHIN 15 YEARS WHICH
WE THINK OF PROEN TOOS IS
REGULATED CLOSER TO THE TIME OF
DEMENTIA ONSET AND THEN BEYOND
[INDISCERNIBLE] PROTEINS THAT
ARE REGULATED WELL, WELL BEFORE
DEMENTIA ONSET.
LET ME BACK UP BECAUSE I WANT TO
EMPHASIZE A FEW THINGS, AT BASE
LINE, PEOPLE WERE IN THEIR 60S
HERE AND NONDEMENTED WHEN WE
MEASURED PROTEINS.
SO WE'RE CONSIDERING THIS LIKE
LATE MIDLIFE AND AGAIN PROTEINS
WERE MEASURED BEFORE PEOPLE
DEVELOP DEMENTIA, WE HAD ABOUT
2000 DEMENTIA CASES OCCUR OVER
THE 25 YEAR FOLLOW UP PERIOD.
NOW 1 THING WE WANTED TO REALLY
TRY TO DRILL DOWN ON IS WHETHER
THESE PROTEINS WERE MIDLIFE
BIOMARKERS, COULD WE FIND
PROTEINS IN 40 AND 50 YEAR-OLDS
THAT PREDICTED A CONDITION THAT
WAS PREDOMINANTLY AFFECTED OLDER
ADULTS.
SO WE SPLIT THE SAMPLE IN HALF,
PARTIC PAPTS BELOW AGE 60, AND
COMPARED THAT OUT OF THE RATIO,
THAT EFFECT SIZE, BETWEEN THOSE
YOUNGER INDIVIDUALS BELOW 60 AND
THE FULL SAMPLE AND REALLY THESE
ESTIMATES STAYED FAIRLY SIMILAR
AND SOMETIMES EVEN STRENGTHENED
SO WE REALLY DO THINK WE HAVE
IT.
SO WE LOOK AT OUR TOP PROTEIN
AND WE ASK WHAT ARE INVOLVE WIDE
THEM, WE SEE THEY'RE RELEVANT TO
PROTEIN COMPLEXIO STASIS AND
FUNCTION AND OTHER BIOLOGIC
PATHWAYS, IT AND THIS WE'RE
HAPPY TO SEE BECAUSE IT IS
SUPPORTED BY GWAS, IMMUNE
DYSFUNCTION COMES OUT PROBABLY
THE MOST, YOU KNOW STRONGLY
ENRICHED PATHWAY, IF YOU LOOK AT
GWAS HITS FOR ALZHEIMER'S
DISEASE, AND WE'RE SEEING SOME
REFLECTION OF THAT DUE TO
PROTEOME, THAT'S LARGELY WHAT WE
SAW IN SOME SYNAPTIC PROTEINS
AND THAT MAKES SENSE AS WELL,
BUT WHAT WAS A MORE INTERESTING
WAY TO UNDERSTAND BIOLOGY OF THE
PROTEOMIC SIGNATURE IN MY
OPINION WAS THE APPROACH TO THE
NETWORK ANALYSIS, MANY OF YOU
ARE FAMILIAR WITH WGCNA, SO WE
AMRI THAD TO OUR MIDDLE AGED
ADULTS.
SO WE CLUSTERED PENAL, WE
CLUSTERED PROTEINS BASED ON A CO
EXPRESSION OR ESSENTIALLY THE
CORRELATION, IT IT'S A BIT MORE
COMPLEX THAN THAT, WHEN WE LOOK
AT GROUPS OF HIGHLY CORRELATED
PROTEINS, WE FOUND 19 DIFFERENT
GROUPS OR MODULES AND WE TOOK
THE FIRST PRINCIPLE COMPONENT OF
EACH OF MODULES AND USE THEM AS
PREDICTERS BUT YOU CAN SEE THEM
AS BEING USED HERE, THIS IS A
BIG MODULE AND THIS IS A SMALL
MODULE HERE AND SO WE RAINCHL IN
SIZE FROM 28-2000.
AND THESE ARE BIOLOGICALLY
RELEVANT, SO WHAT WE DID,
ANNOTATION, OR REPRESENTATION
ANALYSIS STATISTICALLY, WHAT
THESE MODELS REPRESENTED BUT WE
ALSO LOOK AT EACH MODEL
PREDICTED EACH ARREST.
WE HAD 19 OF THEM AND WE HAD
MODULES THAT WERE LEFT OVERS BUT
WE HAD, 1, 2, 3, DIFFERENT
MODELS THAT WERE PREDICTIVE OF
25 DIFFERENT DEMENTIA RISK FOR
ADJUSTING FOR OUR CO VARIANT,
NOW WE SAW A SEPARATE MODULE
WHEN WE LOOKED AT NEAR TERM
DEMENTIA RISK WITHIN 15 YEARS.
SO WE LEGALLY PINNED DOWN THE 4
MODULES AND WE WERE ABLE TO
UNDERSTAND THE BIOLOGY AGAIN
THROUGH OVERREPRESENTATION AND
ANALYSIS, BED THE DIRECTIONALITY
BASED ON HOW THE INDIVIDUAL
PROTEIN AND PATHWAY LOADED ON TO
THE MODULE AND WE'RE ABLE TO
MAKE SOME STATEMENTS ABOUT THE
EVOLVING BIOLOGY LEADING UP TO
DEMENTIA ONSET, SO WHAT I FOUND
WAS INTERESTING WAS THE
IMMUNOLOGIC SIGNATURE, A LOT OF
MODELS HAVE BEEN PREDICTIVE FOR
PROTEINS AND IMMUNE SPECIFIC
PATHWAY, THINGS LIKE JAK STATS
AND THE LANGUAGE THAT'S DOWN
REGULATED AND OTHER IMMUNE
ASSPECS OF FUNCTION WITH THE
GENERAL IMMUNE RESPONSE,
LYMPHOCYTE ACTIVATION AND OTHER
MODELS THAT ARE UPREGULATED.
SO THE COMPLEX IMMUNO DYNAMIC,
AS PEOPLE GET CLOSER AND CLOSER
TO DEMENTIA OBLIGATIONS SET AND
IN--ONSET, AND IN MODEL 19 WE
SEE MORE COAGULATION AND
COMPLEMENT AMONG OTHER THINGS
BEING DISREGULATED.
SO WE'RE ABLE TO LEARN A LITTLE
BIT ABOUT THE BIOLOGY WELLING UP
TO DEMENTIA ONSET.
WE DID A NUMBER OF OTHER THINGS
WE APPLIED 2 SIMPLE MEN DEALIAN
DEALIAN
RANDOMIZATION.
THIS SIGNIFY VERSE SET OF
BIOMARKERS GAZ BEYOND AMYLOID
GOES BEYOND TAU, THAT I
MENTIONED EARLIER AND HERE WE
HAVE BIOMARKERS, IN DYSFUNCTION
SYNAPTIC FUNCTION AND EXTRA
CELLULAR MATE RICK ORGANIZATION
AND VASCULAR PROCESSES THAT ARE
PREDICTIVE OF DEMENTIA, AND WE
THINK ARE YOU KNOW POTENTIALLY
RELEVANT BY O MARKERS IN
MIDLIFE, THEY GIVE US A SENSE OF
DISEASE, HETEROGENEITY AND
HOPEFULLY A WAY IN A MORE
PERSONALIZED WAY UNDERSTAND
WHAT'S DRIVING
DEM-TEBURKEULOSEISIA RISK AS THE
INDIVIDUAL LEVEL NOW WE
UNDERSTAND,--FROM THIS WE GAINED
A LOT OF INFORMATION ABOUT THE
EARLY BIOLOGY, AT LEAST
PERIPHERALLY AHEAD OF DEMENTIA
ONSET BUT WE DON'T YET KNOW HOW
WELL, QUANTITATIVELY THIS
INDIVIDUAL PROTEINS OR THE
COMBINATION PREDICT DEMENTIA
RISK, LIKE DO WE HAVE A TOOL
HERE THAT WE CAN USE FOR PEOPLE
CONCERNED ABOUT THE DEMENTIA
RISK IN THE POPULATION,
PARTICULARLY MIDDLE AGED ADULTS
WHICH IS KIND OF RISKY BUSINESS,
YOU KNOW, YOU DON'T WANT TO
MISPREDICT SOMEONE IN THEIR 40S
AS BEING IMMINENTLY AT RISK FOR
DEMENTIA AND HAVE A LARGE AND
EKING 95 IMPACT ON THEIR LIFE.
SO WE TESTED OUR--WE BUILT A
PROTEIN RISK SCORE TO PREDICT 20
YEAR RISK, USING THIS HERE AND
CAME DOWN TO RUNNING A SIMILAR
ANALYSIS, YOU KNOW WITHOUT THE
ADJUSTMENT BECAUSE WE'RE
INTERESTED IN APPROACHING
PREDICTIVE POWER, AND WE USE IT
WITHIN CROSS VALIDATION AND
THAT, WE DERIVED THE OPTIMIZED
25 PROTEIN MODULE AND THIS IS
FROM A 70% TRAINING SET.
SO WE'RE USING THE SAME COHORT,
BUT THEN WE TUNED IT AND TESTED
IT IN 15% AND 15%, THE REST OF
THE COHORT AND SO FROM THIS WE
GOT THE 25 PROTEIN COMPOSITES
FOR WHICH YOU WILL SEE REFERRED
TO AS THE DEMENTIA SOMA SIGNAL
TEST OR THE SST, THAT'S
PREDICTIVE TO AN EXTENT OF 20
YEAR DEMENTIA, AND WE WERE ABLE
TO DEFINE SOMEONE'S ABSOLUTE 20
YEAR REZ AND PUT PEOPLE INTO 4
RISK BIN ANDS THIS WAS WORK THAT
WAS LED BY CLAIR PATTERSON AND
MICHAEL DUG AN WHO IS A POST DOC
IN MY LAB.
SO HERE'S THE RESULTS FROM THE
TRAINING AND VALIDATIONS SHOWN
ON THE ROC CURVE BUT THE BOTTOM
LINE THE TEST JUST 25 PROTEINS
BY THEMSELVES, THE AUC, FOR
DEMENTIA PREDICTION WAS .73, SO
IT'S NOT EXCELLENT, IT'S LIKE
OKAY.
NOTHING TO WRITE HOME ABOUT BUT
WE HAVE TO RECOGNIZE WHAT WE'RE
PREDICTING WITH THAT 20 YEARS
INTO THE FUTURE AND THERE'S A
LOT OF COMPETING THINGS THAT CAN
HAPPEN TO AN INDIVIDUAL OVER
THOSE 20 YEAR PERIOD.
SO IN THAT CONTEXT, IT'S OKAY,
AGE OBVIOUSLY THE STRONGEST RISK
DEMENTIA FACTOR RELEVANT BUT NOT
SO CLINICALLY RELEVANT.
HOW DO WE DO WHEN WE COMBINE AGE
WITH THE SOMA SIGNAL TEST, WELL
THEN WE GET INTO PREDICTABLE
ACCURACY NUMBERS WHERE WE SEE AN
APPOINTEE, SO WE THINK WITH
THESE 25 PROTEINS PLUS KNOWING
AN INDIVIDUAL'S AGE, WE CAN DO
FAIRLY WELL IN PREDICTING YOUR
20 YEAR DEMENTIA RISK AND THIS
OUT PERFORMS THE MAJOR DEMENTIA
RISK GENE JUST IN COMPARISON BUT
I WILL MENTION OTHERS LEALTER.
SO I MENTIONED WE STRATIFIED
PEOPLE INTO QUAR TILES, WE PUT
PEOPLE AT MEDIUM LOW AND MEDE
HIGH RISK BINS AND WE WERE ABLE
TO SEE HOW MUCH MORE LIKELY YOU
WERE TO DEVELOP DEMENTIA IF YOU
WERE PUT IN THE HIGH RISK BIN
COMPARED TO THE LOW RISK BIN AND
THAT DIFFERENCE WAS ALMOST 10
FOLD, 9-10 FOLD, WHERE YOU SEE
HERE THE PERSPECTIVE PLOT, IF
YOU WERE THE LOW RISK THEN,
WELL, IF YOU WERE IN THE HIGH
RISK BIN, YOU HAD 10 TIMES MORE
HIGHER LIKELIHOOD OF DEVELOPING
DEMENTIA OVER THE 20 YEAR PERIOD
THAN SOMEONE IN THE LOW RISK,
THEN, SO WE THINK THERE'S QUITE
A BIT OF CERTAINTY AT LEAST
ESPECIALLY IN THESE HIGH AND LOW
RISK CATEGORIES OF PERSONS OF
LESS CERTAINTY HERE.
OKAY, SO WHAT ABOUT OTHER
BENCHMARK.
HOW WELL DOES IT DO AGAINST
QUOTE-UNQUOTE GOLD DEMENTIA
PREDICTORS OF RISK.
RIGHT NOW WE HAVE THIS IN THE
PATHOGENESIS, WELL, ANOTHER
EXCITING THING THAT'S HAPPENING
IN ALZHEIMER'S DISEASES IS THESE
PROTEINS HAVE BEEN, YOU KNOW
MEASURABLE, NOW IN BLOOD, PRETTY
ACCURATELY AND SO THERE'S A LOT
OF EXCITEMENT ABOUT THE ABILITY
TO PREDICT ALZHEIMER'S DISEASE
OR IDENTIFY ALZHEIMER'S DEC
USING BLOOD TESTS, YOU MAY HAVE
HEARD ABOUT THIS IN YOUR OWN
WORK OR IN THE LAY MEDIA, BUT WE
TOOK SOME OF THESE, YOU KNOW AND
ACKNOWLEDGED THESE ARE NOT THE
STATE-OF-THE-ART NOW, BUT WHEN
WE STARTED THIS STUDY, THEY
WERE, THIS AMYLOID DATA MEASURE
AND TAU, PTAU181, THIS IS A TAU
PHOSPHO TYPE, AND WE COMPARED
THEM TO OUR DEMENTIA SOMA SIGNAL
TEST.
YES, QUESTION?
DID EMPLOY [INAUDIBLE QUESTION
FROM AUDIENCE ] PREDICTIVE
MODEL?
NO WE HAVEN'T.
[INAUDIBLE QUESTION FROM
AUDIENCE ] IT IS, IT IS BUT IT'S
NOT SOMETHING, SO WE'RE TRYING
TO HAVE A TOOL HERE THAT WE
QUITE GENTLEMENLY IF IT MEETS A
STANDARD, NOT NECESSARILY OUR
STANDARD BUT FAMILY HISTORY IS 1
OF THE THINGS LIKE A LOT OF
PEOPLE DO HAVE ISSUES SAY YOUR
PATIENT DIES AT 50, 60, YOU KNOW
THEY MAY DIE BEFORE THEY HAVE A
CHANCE TO EXPRESS THE
DEMETROPOLITANNIA ITSELF, SO A
LOT OF FAMILY HISTORY OF
DEMENTIA THAT'S NOT NECESSARILY
THERE, ESSENTIALLY, YOU KNOW
LIKE MY MOM'S FIERGT DIED AT 50
SO WE DON'T KNOW IF HE WOULD
HAVE DEVELOPED ALZHEIMERS, IT
DOES IPT GREATER CREASE YOUR
RISK FOR ALZHEIMER'S DISEASE AND
A LOT OF THAT IS DRIVEN BY
APO-E, POSSESSION WHICH IS THE
MAJOR RISK JEAN.
YOU CAN THINK OF THIS AS A
PROXY, YEAH, SO YEAH, TO THAT
EXTENT, LIKE WE TRY TO
INCORPORATE THE BASE OF THE
PREDICT OR AND WE DID OUT
PERFORM THAT AND WE DIDN'T FILL
THEM UP BECAUSE WE WANTED THEM
TO BE AS EASY AS POSSIBLE.
SO HOW DID THE 2 COMPARED TO THE
STATE-OF-THE-ART MEASURES OR
FOREMOST STATE-OF-THE-ART
MEASURES, SO IT DOES OUT
PERFORM EACH OF THEM AND IT OUT
PERFORMS THE COMBINATION, YOU
SEE, WE'RE STILL HOVERING AT
ABOUT .7 HERE WITH THE PROTEINS
ALONE AND IT OUT PERFORMS THE
BIOMARKERS WHICH ARE THESE 4
PROTEINS IN COMBINATION AND WHEN
THEY'RE ALSO TOGETHER, WE GET A
LITTLE BETTER AS WELL EMPLOY SO
WE'RE BEATING AMYLOID, AND TAU
ITSELF WHEN PREDICKING
CLINICALLY RELEVANT DEMENTIA CAN
WE THEN WANTED TO KNOW, OKAY,
HOW WAS THE SCORE APPLIED TO
OLDER ADULTS AND IT SEEMS TO DO
BETTER THERE, WHEN YOU BRING THE
SCORE AND APPLIED TO 60, 70, 80
YEARS OLD, THOSE IN THE HIGH
RISK BIN ARE ABOUT 13 TIMES
HIGHER OR MORE LIKELY TO DEVELOP
DEMENTIA OVER THIS 5 YEAR
PERIOD, THAN THOSE IN THE LOW
RISK BIN.
SO WE'RE HAPPY TO SEE THAT AND
THIS IS WITHOUT ANY
RECALIBRATION OR THIS LATER LIFE
PERIOD AND AGAIN IT OUT
PERFORMED, YOU SEE EVERYTHING A
LITTLE BIT BETTER HERE BUT OUR
MEASURES STILL OUT PERFORMED
THE STANDARD GOLD MEASURES AND
IN COMBINATION, THEY DO REALLY
WELL.
SO WE TOOK IT OUT OF SAMPLE AND
THE STUDY ARE AGING WHICH IS A
COHORT WE HAVE AT NIA AND LOOKED
AT IT WITH EBD O PHENOTYPES MRI
AND SPECIFICALLY MEASURES OF
VOLUME, AND YOU KNOW WHAT WE'RE
SHOWING HERE IS THAT, YOU KNOW
THIS RISK SCORE IS PREDICTIVE OF
BOTH SMALL AND BRAIN VOLUME BUT
ALSO BRAIN ATROPHY IF WE LOOK AT
IT, AND IF WE LOOK TO SEE WHICH
ASPECTS OF THE BRAIN IT ACTUALLY
PREDICTIVE OF, IT'S MEDIAL
TEMPORAL HIPPOCAMPAL REGION
WHICH IS ACTUALLY WHERE WE SEE A
LOT OF THE ATROPHY AND
NEUROPATHOLOGY IN ALZHEIMER'S
DISEASE.
I WAS SPECIAL ASSURANCE THAT WE
WERE BARKING UP THE RIGHT TRAIT.
SO HOW PREDICTIVE WAS THE
AMYLOID, SO THIS IS A KEY
PROTEIN AGGREGATE IN ALZHEIMER'S
DISEASE AND ACTUALLY THE TARGET
OF SOME OF THESE THERAPIES,
WELL, IT IS THE TARGET FOR THE 2
THERAPIES THAT WERE MORE
RECENTLY APPROVED TREATMENT FOR
ALZHEIMER'S DISEASE, SO IT DOES
OKAY BUT IT ACTUALLY UNDER
PERFORMS THE ACTUAL MEASURE OF
AMYLOID, WHICH IS WHAT WE MIGHT
EXPECT, IN COMBINATION THOUGH,
IT DOES ACTUALLY DO QUIT WELL,
YIELDS BETTER PREDICTION, FOR
AMYLOID POSITIVE STATUS, BUT WE
WOULDN'T PROPOSE TO USE IT TO
MEASURE AMYLOID WHEN CAN YOU
JUST MEASURE THE AMYLOID SOLUBLE
AMYLOID LEVELS IN BLOOD ITSELF,
SO I WILL SKIP THROUGH THIS
SUMMARY, BUT SOME OF THE USE
CASES ARE IMPORTANT TO TALK
ABOUT, TRIAL ENRICHMENT IS A BIG
DEAL FOR ALZHEIMER'S DISEASE, OR
DEMENTIA DRUG TRIALS BECAUSE
THE--YOU KNOW IT'S A VERY
GRADUAL CONDITION, THE TRIALS
HAVE TO BE VERY LONG AND VERY
LARGE ESPECIALLY IF YOU START
TREATING PEOPLE EARLY BEFORE
THEY VISIT VERY SIGNIFICANT
SYMPTOM, COGNITION TENDS TO BE
THE END POINT THAT THE FDA WILL
APPROVE THE DRUG FOR, AND WE'RE
INTERESTED IN USING FOR THEIR
PHASE 3 PIVOTAL TRIAL.
SO IF WE CAN FIND PEOPLE WHO ARE
IMMINENTLY ABOUT TO DECLINE, OR
ARE AT HIGHEST RISK FOR ACTUAL
CLINICAL DEMENTIA ONSET THEN WE
CAN ENRICH OUR TRIAL EVEN IF
WE'RE ENROLLING COGNITIVE
PEOPLE, EVEN IF THEY'RE IN THE
HIGH RISK BEN, WE COULD SAY WITH
ADDITIONAL CERTAINTY THAT THE
PERSON WILL DECLINE AT THEIR
GIIVE TRAJECTORY, LET'S PUT THE
PERSON IN THE TRIAL AND SEE IF
WE CAN SLOW THAT VERSUS THE
PLACEBO.
SO THIS WILL REDUCE SCREEN
FAILURES AS WELL, AND YOU KNOW
THINKING FURTHER ALONG, IT MAY
BE ACTUALLY USE THE PROXY END
POINT IF WE CAN'T OR DON'T HAVE
ENOUGH TIME OR NOT POWERED TO
MEASURE COGNITIVE CHANGES, OR
TARGETING PEOPLE IN THE FIFTH
DECADE OF LIFE, BUT WE DON'T
EXPECT CHANGES, YOU MAY BE ABLE
TO USE THIS AS A PROXY END POINT
TO SEE IF, HEY, YOU'RE
INTERVENTION ACTUALLY MOVES THE
NEEDLE IN TERMS OF REDUCING
DEMENTIA RISK, YOU KNOW FURTHER
ALONG AS INDIVIDUALS AGE.
SO NOW I'M GOING TO SWITCH GEARS
AND TALK ABOUT ANOTHER
APPLICATION, WHERE I MENTIONED
EARLIER IN MY INTEREST IN THE
IMMUNE SYSTEM AS IT RELATES TO
ALZHEIMER'S DISEASE AND 1 OF THE
THINGS THAT HAS BECOME FAIRLY
APPARENT ESPECIALLY IN WAKE OF
COVID IS THAT INFECTION AND
IMMUNE ACTIVATION ISN'T SEVERE
INFLAMMATORY INSULTS CAN AFFECT
BRAIN FUNCTION.
SO I WANTED TO UNDERSTAND THIS
LINK WE'RE SEEING BETWEEN HAVING
AN INFECTION AND RISK FOR
DEMENTIA ONSET AND SO TO BE
CLEAR THOUGH I'M TALKING ABOUT
SEVERE INFECTIONS NOT YOUR
COMMON COLD.
SO REST ASSURED THAT, YOU KNOW
CATCHING THE--WELL, I'M NOT
GOING TO EVEN SAY THAT, CATCHING
A COLD WILL NOT PUT YOU AT RISK
FOR DEMENTIA BUT THERE IS
EVIDENCE THAT THESE MAJOR
INFECTIONS PARTICULARLY AMONG
OLDER ADULLS SEEM TO BE RISK
FACTORS, SO THIS IS JUST TO SHOW
THAT IMMUNE ACTIVATION CAN
INFLUENCE DEMENTIA RISK IN TERPS
OF DIRECTIONALITY, THAT IS
DEPENDENT ON THE CONTEXT BUT WE
CAN--I CAN SEPARATE THESE IMMUNE
EXPOSURES, DIET VERSUS ACUTE
SURGERY, ACUTE INFECTION, TISSUE
DAMAGE TO AN INJURY, THESE ALL
HAVE IN COMMON THAT THEY
STIMULATE THE IMMUNE SYSTEM, YOU
KNOW P A MPs, ET CETERA, THEY
STIMULATE THESE AND EVENTUALLY
ADAPT TO THE IMMUNE CELLS AND WE
THINK THROUGH VARIOUS PATHWAYS
THEY CAN INFLUENCE THE BRAIN
FUNCTION.
SO THIS HAS BEEN JUST THE
PATHWAYS I TALK ABOUT, BUT AGAIN
WE HAVE THIS INFLAMMATION,
THINGS THAT ARE CHRONIC, ACUTE,
AND WHAT THEY HAVE IN COMMON IS
THE REGULATION, THESE ARE
CYTOKINES, CHEMOKINES, THESE ARE
THE 1S WE KNOW OF, OTHERS ARE
IDENTIFYING PLENTY OF IMMUNE
PROTEINS THAT TEND TO BE
RELEVANT AS WELL, BUT THE IDEA
IS THAT THEY CAN INFLUENCE BRAIN
FUNCTION EITHER THROUGH CROSSING
THE BLOOD BRAIN BIRRIER
SURFACESSIER DIRECTLY,
INDIRECTLY BY STIMULATING
ENDOTHELIAL CELLS WHICH THEN CAN
TRANSMIT SIGNALING TO MICROGLIAL
OR ASTRO SIGHTS FOR EXAMPLE ON
THE OTHER SIDE OF THE
VASCULATURE, BUT ALSO THROUGH
THESE THINGS CALL VENTRICULAR
ORGANS LIKE THE PLEXUS WHERE
THERE'S ACTUALLY PLACES STUFF IN
THE BLOOD TO COMMUNICATE WITHIN
THE BRAIN STEM AND THEN THROUGH
THE VAGUS NERVE AS WELL.
SO THERE IS, DESPITE BLOOD BRAIN
BARRIER WHICH IS A REAL THING,
THOSE CERTAINLY KEEP THE BRAIN
PROTECTED FROM THE VARIOUSIATION
AND CONTENTS OF BLOOD, THERE ARE
STILL QUITE A FEW MECHANISMS FOR
PROTEINS IN CIRCULATION TO
INFLUENCE BRAIN FUNCTION AND I
ALWAYS MENTION THIS TO PEOPLE,
EVERY TIME YOU GET SICK, YOU
FEEL DIFFERENTLY, YOU STOP
EATING SO MUCH, YOU FEEL
APATHETIC, YOU LOSE MOTIVATION,
THAT'S AN EXAMPLE OF PROTEINS IN
CIRCULATION, AND WHAT VPIL6 OR
TNF ALPHA ACTUALLY INFLUENCING
YOUR BEHAVIOR, AND THE
BEHAVIORIAL INFLUENCE IS EXERTED
THROUGH THE EFFECT ON THE BRAIN
ITSELF, THIS HAPPENS TO US ALL
THE TIME.
YOU KNOW ACUTE INFLAMMATORY
INSULT IS HAPPENING AT MUCH
HIGHER LEVELS AND MANY FOLDS,
AND HIGHER IN TERMS OF
MAGNITUDE.
BUT I'LL MOVE ON SO THERE'S BEEN
QUITE A BIT OF EVIDENCE LINKING
INFECTION HISTORY WITH DEMENTIA
RISK, SO WE DID SOME WORK
EARLIER SHOWING THAT HISTORY OF
HOSPITALIZATION, ALSO CRITICAL
ILLNESS AND INFECTION IN
PARTICULAR SEEM TO BE ASSOCIATED
WITH VOLUME LOSS IN THE FUTURE
AND THEN THERE'S QUITE A BIT OF
WORK SHOWING THAT HAVING HISTORY
OF MAJOR INFLAMMATORY EVENTS
LIKE CRITICAL ILLNESS,
HOSPITALIZED INFECTION, YOU KNOW
THESE THINGS AGAIN TEND TO
INCREASE AND RISK WITHIN THE
NEXT FEW DECADES.
WAS THERE A QUESTION?
NO?
SO THIS IS 1 RECENT PAPER THAT I
LIKE WHICH DID THIS REALLY WELL
AND USED THE UK BIOBANK DATA, IT
USED DATA FROM THE FINISHED
MULTICOHORT SO 2 BIG LARGE
STUDIES BUT THEY LOOK AT HISTORY
OF ANY INFECTION, VIRAL
INFECTION, HOW DOES THIS WORK
FOR 4 DIFFERENT TIMES OF
DEMENTIA AND IRRESPECT
EVALUATION PROCESS OF WHETHER
IT'S BACTERIAL OR VIRAL, HAVING
AN INFECTION DOES INCREASE
DEMENTIA RISK, PARTICULARLY
VASCULAR DEMENTIA WHICH WAS IN
PARKINSON'S DISEASE DEMENTIA, SO
YOU KNOW WE FOCUS ON ALL COST
DEMENTIA WHICH ARE STILL
INCREASED POST INFECTION, BUT IT
SEEMS LIKE THE VAST PART OF
PATHOGENESIS IS PARKINSON'S IS
THE MOST SUSCEPTIBLE HERE, BUT
THE THING I WANT TO EMPHASIZE
HERE IS THAT THIS STUDY LOOKEDDA
THE LONG-TERM FOLLOW UP SO 10
YEARS, 10 YEARS, 15 YEARS, SO
MAY HAVE GONE TO 20 BECAUSE
THERE'S ALWAYS THIS REVERSAL
CAUSATION, PEOPLE AT RISK FOR
DEMENTIA ESPECIALLY IF THEY'RE
PROBABLY WITHIN YEARS OF
DEVELOPING DEMENTIA OR PROBABLY
MORE SUSCEPTIBLE TO INFECTIONS
THEMSELVES, SO YOU HAVE TO
SEPARATE OUT, IT'S DEMENTIA
MAKING SOMEONE SUSCEPTIBLE IN
DEMENTIA AND IF WE CAN LOOK AT
INFECTION, 20 YEARS BEFORE
DEMENTIA ONSET WE CAN SAY, OKAY,
IT'S LIKELY NOT THE DEMENTIA OR
THE DEMENTIA PATHOGENESIS THAT'S
MAKE THANKSGIVING PERSON
SUSCEPTIBLE TO AN INFECTION 20
YEARS BEFORE THE DEMENTIA
EXPRESSES ITSELF, IT'S MORE
LIKELY THE OPPOSITE ISSUES THE
IONIZATION FEKS MAY LAY THE
GROUND WORK FOR DEMENTIA RISK.
SO THIS COMES TO THE FOREFRONT
OF OUR CONSCIOUSNESS WITH COVID,
LONG COVID WE THINK IS AN
EXAMPLE OF THIS SO HAD IS JUST
SOME REALLY GOOD EXAMPLES OF
THIS TOPIC FOR IT COHORT.
THIS IS THE UK BIOBANK AS WELL,
THIS IS A LONGITUDINAL ANALYSIS,
AND THEY LOOK AT PEOPLE WITH A
EFTHIMIOSY OF COVID INFECTION
VERSUS THOSE WHO ARE--WHO DIDN'T
HAVE A COVID INFECTION HISTORY
AND THEY FOUND OVER TIME THOSE
WITH A HISTORY OF SARS-COV-2 IN
THESE HIGHLIGHTED AREAS OF THE
BRAIN, SO WHEN THEY LOOK AT
ACTUAL SEVERITY, LIKE IT'S OKAY,
WE'RE GOING TO TAKE EVERYONE
WITH AN INFECTION AND COMPARE
HOSPITALIZED WITH
NONHOSPITALLIZED INDIVIDUALS AND
THEY FOUND EVEN FURTHER
INCREASES IN VOLUME LOSS AMONG
THOSE WITH MORE SEVERE INFECTION
AND THE SEPARATION BETWEEN
BASICALLY THE CASES AND CONTROLS
SEEM TO WIDEN AS PEOPLE AGE.
SO THIS AFFECT WAS MUCH STRONGER
IN LATER SETS OF IN LIFE THAN IT
WAS AMONG 40 AND 50 YEAR-OLDS AS
I SLEEP APNEA AND OBESITYY HERE.
SO THAT'S 1 EXAMPLE, HERE'S
ANOTHER COVID EXAMPLE THAT I
THINK IS ILLUSTRATIVE OF AN
IMPORTANT POINT SO SARS-COV-2
AND AVI NATH HAVE DONE THIS
WORK, SARS-COV-2 IN MOST CASES
DOES NOT ENTER THE BRAIN.
SO MEN WITH HIGHER THEY LOOK AT
CSS, OR SPINAL FLUID, I DON'T
KNOW HOW MUCH AUTOPSIES THEY'VE
DONE BUT THERE DOESN'T SEEM TO
BE A LOT OF VIRUS IN THE BRAIN
BUT THAT--AND THAT'S ILLUSTRATED
BY THIS LACK OF ELEVATED CELL
COUNT IN CEREBRAL SPINAL FLUID
HERE, THIS IS JUST A CASE HERE,
FROM VERY EARLY ON BEFORE THEY
HAD BIG NUMBERS, BUT WHAT--WHAT
IS APPARENT IN PEOPLE WITH
SARS-COV-2 IS THEY HAVE SPIKES
AND INFLAMMATION, THAT
INFLAMMATION OUTSIDE THE CENTRAL
NERVOUS SYSTEM IN THE BLOOD AS
MEASURED HERE BY V-REACTIVE
PROTEINS SO TYPICALLY 3 IS THE
CUT OFF FOR AT LEAST CHRONIC
INFLATION, LOW GRADE
INFLAMMATION, BUT IF YOU HAVE A
LEVEL ABOVE 3, IT'S NOT A GOOD
THING, HERE EVERYBODY'S ABOVE A
HUNDRED SO THIS IS AN ACUTE
INFLAMMATORY EVENT AND WHEN I
MENTION THIS IS LIKE MANY TIMES
HIGHER MAGNITUDE THAN THE LOW
GRADE INFORMATION THAT MAY ALSO
BE A RISK FACTOR BUT BEYOND CRP,
AND THIS IS IN BLOOD, WE SEE
EVIDENT OF ACTIVATED IMMUNE
CENTRAL IMMUNITY AND THE BETA 2
MICROGLOBUE LYNN, SO THE TAKE
AWAY HERE IS ALTHOUGH THE VIRUS
DOESN'T ENTER THE BRAIN, THERE'S
STILL A CENTRAL IMMUNE RESPONSE
AND WE THINK THIS IS MEDIATED
THROUGH THE PATHWAYS OF
INTERVENTION, THOSE VARIOUS
CONDUITS, SO WE RECENTLY
PUBLISHED THIS PAPER IN NATURE
AND AGING WHICH IS PRIOR TONING,
WHAT IS THE MOLECULES THAT'S
MEDIATE THIS RELATIONSHIP.
YES?
>> [INAUDIBLE QUESTION FROM
AUDIENCE ]
>> YEAH, EXCELLENT QUESTION.
AND SO SOMETHING THAT WE LOOKED
AT HERE.
BUT IN THE PAPERS I SHOWED
BEFORE THAT I MENTIONED COVID,
THAT IS ALL PREPANDEMIC AND SO,
YOU KNOW IF YOU TAKE PEOPLE WITH
A HISTORY OF HOSPITALIZED
INFECTION, WHETHER IT BE
PNEUMONIA, SEPSIS, OR SOMETHING
ELSE, THOSE SEEM TO BE RISK
FACTORS AS WELL.
AND SO MY--I STILL THINK THIS,
THERE MAY BE DIFFERENCES BETWEEN
COVID AND SOME OF THESE OTHER
MORE SEVERE COVID OR OTHER
SEVERE INFECTIONS IN TERMS OF
THE THE ACTUAL IMMUNE RESPONSE,
I THINK THERE A PATHWAY THAT
UNITES THEM AND REALLY
PERIPHERAL INFLAMMATION, IT
SEEMS TO BE LIKE A LOT OF
INTERFERON TYPE 1, TYPE 2
INTERFERON APGHTIVATION, SO I
THINK THEREYA MORE IN COMMON
THAN THE DIFFERENCES BETWEEN
THEM AND HERE, THIS PAPER, WE
LOOKED AT A NUMBER OF
INFECTIONS, NONE OF WHICH WERE
COVID, PROBABLY THE 1S THAT HAVE
BEEN AROUND FOR, WELL, YOU KNOW,
THAT WE'VE BEEN TREATING FOR A
LONG, LONG TIME, ACTUALLY LET ME
BACK UP, SO LET ME JUST GO
THROUGH THIS FRAMEWORK HERE
BECAUSE THIS IS WHAT THE STUDY
WAS BASED ON.
AND THIS WAS AGAIN LED BY
MICHAEL DUGG,A N, THE POST DOC
IN MY LAB.
THIS WAS MANYIERS OF WORK, WE
RECENTLY GOT THIS PUBLISHED AND
WE WERE SUPER EXCITED ABOUT IT
BUT THE IDEA THAT WAS THAT
INFLECTION INFLUENCES
NEURODEGENERATION BY INFLUENCING
THIS EXPRESSION OF IMMUNE
PROTEINS THROUGHOUT CIRCULATION
AND AGAIN THESE PROTEINS GO
THROUGH THE VARIOUS CONDUITS
INFLUENCE MOLECULAR CHANGES IN
THE BRAIN INCLUDING NEURAL
INFLAMMATION, PROMOTING AMYLOID
AND TAU WHICH I TALKED ABOUT AS
TETERMINANTS OF ALZHEIMER'S
DISEASE, AND EVENTUALLY YOU GET
BRAIN ATROPHY AND
NEURODEGENERATION AND A COG
95ATIVE SYMPTOMS THAT MANIFEST
WITH DEMENTIA SO THAT'S THE
FRAMEWORK AND WE SET OUT TO TEST
PRETTY MUCH EACH OF THESE ARROWS
IN THE STUDY, SO WE FIRST WENT
FROM THE BEGINNING TO THE VERY
END, IT DOES INFECTION, PEOPLE
WITH INFECTION HISTORY HAVE
EVIDENCE OF NEURODEGENERATION
AND THIS IS LONGITUDINAL BRAIN
VOLUME LOSS SO WE LOOK AT THAT
OF THE BALTIMORE LONGITUDINAL
STUDY OF AGING AND LOOK AT THIS
SET OF 10-15 INFECTION AND
LOOKED AT EACH 1 OF THEM IN
RELATION TO VOLUME LOSS AND
VARIOUS BRAIN REGIONS, AND
HERE'S JUST 2 INFECTIONS AS AN
EXAMPLE SO INFLUENCA WE SEE A
GENERAL TRANSFER, LIKE PEOPLE
WITH A HISTORY OF INFLUENZA TO
HAVE A STEEPER LOSS OF VOLUME
ACROSS VARIOUS BRAIN REGIONS,
THIS IS TOTAL BRAIN,
NONSIGNIFICANT IF YOU LOOK AT
TEMPORAL LOBE OR OCCIPITAL LOBE,
IT DOES CROSS THE THRESHOLD OF
SIGNIFICANCE AND THERE'S A TREND
THAT SUGGESTS IT'S NOT A GOOD
THING FOR THE BRAIN.
WE LOOK AT SKIN AND SUBCUTANEOUS
INFECTIONS, THINGS LIKE
CELLULITIS, INFECTIOUS SKIN,
YEAH, I GUESS, INFECTIONS OF THE
SKIN, AND THIS IS ACTUALLY--IT'S
INTERESTING WHAT FALLS IN THIS
CATEGORIES BUT IT'S BECOME VERY
RELEVANT AND CLEAR THAT THIS IS
SOMETHING THAT'S A CONSISTENT
RISK FACTOR FOR DEMENTIA AND IT
SURPRISED ALL OF US, BUT IF YOU
LOOK AT PEOPLE WITH A EFTHIMIOSY
OF SKIN AND SUBCUTANEOUS
INFECTIONS THEY SEEM TO BE
SUSCEPTIBLE TO TOTAL BRAIN LOSS
IN VOLUME GRAY MATTER WITH
DIRECTIONALITY ACROSS THE
REGIONS OF INTEREST, AND SO WE
LOOK BACK, WELL, MANY ADDITIONAL
INFECTION TYPES AND THESE ARE
THE 6 WHERE WE SAW AT LEAST 1
BRAIN REGION SHOW SOME
STATISTICAL SIGNIFICANCE SO WE
FOCUSED ON THESE 6 TYPES OF
INFECTIONS OF UPPER RESPIRATORY
INFECTIONS FROM THE VIRAL
INFECTION GROUP AND THE YOU HAD
HHV, THE HUMAN HERPES VIRUS
WHICH THERE'S BEEN QUITE A BIT
OF MIXED EVIDENT OF ITS ROLE OR
LACK THEREOF IN DEMENTIA SO
ESTABLISHING THESE 6 SECTIONS
WAS NOT CROSSED OFF ARE
ASSOCIATED AT LEAST IN OUR HANDS
WITH BRAIN ATROPHY, WE WANTED TO
SEE OKAY, ARE THEY ASSOCIATE
WIDE DEMENTIA RISK, SO WE WENT
TO THE BIOBANK, TO THE
MULTICATEGORY COHORT AND
CATEGORIZED THESE IN OUR INITIAL
TOEVERY COHORT AND FOUND
A--OKAY, THOSE INFECTIONS IN
ADDITION TO BEING ASSOCIATE WIDE
BRAIN VOLUME LOSS IN THE
BALTIMORE LONGITUDE FLAL STUDY
OF ANALLING ARE PREDICTABLE
DEMENTIA RISK OVER A 20 YEAR
FOLLOW UP PERIOD AND YOU IMAIF
BIOBANK.
SO SOME OF THESE WE DIDN'T HAVE
ENOUGH CASES TO LOOK AT BUT
ESSENTIALLY EACH OF THE
INFECTIONS WERE ASSOCIATED WITH
ALL CAUSE DEM-TEBURKEULOSEISIA
AND THEN WE SAW AGAIN--DEMENTIA
AND THEAN WE SAW AGAIN FOR THE
STUDY FOR THE VASCULAR DEMENTIA
COMPARED TO ALDZ JEIMER'S
DISEASE.
OKAY, SO WE ESTABLISHED THEN
THAT THESE INFECTIONS ARE
ASSOCIATED WITH ATROPHY, ARE
ASSOCIATED WITH DEMENTIA RISK.
SO THEN WE WANTED TO UNDERSTAND
WHAT--WHAT IS THE PROTEOMICS
SIGNATURES NAIFURE, LIKE WE'RE
REALLY AFTER THE PROTEOMIC
MEDIATORS HERE THAT MIGHT, YOU
KNOW LEAD SOMEONE WITH AN
INFECTION HISTORY TO DEVELOP
DEMENTIA RISK, AND AN IMPORTANT
POINT THIS IS INFECTION HISTORY
AND IT NOT NECESSARILY, WE'RE
NOT TAKING BLOOD IN THE ACUTE
PHASE SO THIS IS PEOPLE WITH,
YOU KNOW WHO MAY HAVE HAD AN
INFLUENZA EVENT 14 YEARS EARLIER
THAT WAS CAPTURED IN OUR STUDY,
YOU KNOW SOMETIME LATER WE
MEASURE THEIR BLOOD AND DID
PROTEOMIC ANALYSIS, AND I THINK
14 OR 10, SOMEWHERE AROUND THERE
MAY HAVE BEEN THE ACTUAL GAP
BETWEEN THE INFECTION, YOU KNOW
THE INDEMNIFICATION INFECTION
AND THE MEASUREMENT OF BLOOD IN
THE MEASUREMENT OF MRI SCANS,
THESE ARE REMOTE INFECTIONS.
SO WE LOOKED AT EACH OF OUR 6
INFECTIONS IN RELATION TO
HISTORY IN RELATION TO THE
PROTEOMICS SIGNATURE AND WHAT WE
SAW WAS INFLUENZA IN PARTICULAR
HAD A VERY STRONG PROTEOMICS
SIGNATURE THAT PEOPLE WITH A
HISTORY OF THE FLEW HAD A STRONG
OR HAD UP AND DOWN REGULATION OF
VARIOUS PROTEIN, SKIN AND
SUBCUTANEOUS INFECTIONS, THE
OTHER EXAMPLE, WE SAW A WEAKENED
PROTEOMICS SIGNATURE, THERE WERE
LESS OF THESE PEOPLE, IT WAS A
POWER ISSUE, AND WE SAW
INTERESTING PROTEINS AND SOME OF
WHICH WE SAW WERE ALREADY THERE
LIKE APO-E, LOOKING AT SIGNATURE
FOR ALL 6 AND SHOWING THAT HEY,
THERE ARE SOME PROTEINS THAT ARE
UPAND DOWN REGULATED
CONSISTENTLY ACROSS VARIOUS
INFECTION TYPE, WE WANTED--WE
THEN TRY TO UNDERSTAND, ARE
THESE PROTEIN, DO THESE PROTEINS
MEDIATE THIS RELATIONSHIP
BETWEEN INFECTION AND
NEURODEGENERATION, SO WE TRIED
TO FIND PROTEINS THAT WERE
DISREGULATED IN PEOPLE WITH AN
INFECTION HISTORY AND ASSOCIATED
WITH NEURODEGENERATION, AND THEN
FOR THOSE WE LOOKED AT THE THE
MOLECULAR SIGNATURE AS WELL TO
SEE IF THEY WERE RELATED TO THE
BRAIN DEMENTIA UNDERLYING RISK.
SO WE'RE TRYING TO BRING IT ALL
TOGETHER.
SO THIS IS AN EXAMPLE OF THE
CANDIDATE PROTEIN WE IDENTIFIED
FOR 1 OF OUR INFECTIONS SO
LOOKING AT THE FLEW HERE FOR
WHICH WE HAD MANY CASES WE HAD
GOOD POWER, BUT EVERYTHING IN
THIS PLOT WAS WHAT WE CONSIDER A
CANDIDATE PROTEIN, CANDIDATE
MEANING IT WAS ASSOCIATED WITH
AN INFLUENZA HISTORY AND
ASSOCIATED WITH FUTURE EITHER,
FUTURE BRAIN ATROPHY, EITHER IN
A PROTECTIVE OR PATHOGENIC WAY.
SO, THESE PROTEINS FOR EXAMPLE
IN THIS TOP QUADRANT WERE
ELEVATED IN PEOPLE WITH A
HISTORY OF THE FLU AND
ASSOCIATED WITH BRAIN VOLUME
LOSS.
THESE PROTEINS IN IN QUADRANT
WERE DOWN REGULATED WITH PEOPLE
IN THE HISTORY AND ASSOCIATED
WITH LESS BRAIN VOLUME, AND
THESE ARE PATHOGENIC IN
PROPROTEINS RESPECTIVEY SO WE
MET BOALGT OF THOSE CRITERIA AND
WE WANTED TO UNDERSTAND THE
MOLECULAR SIGNATURE LINKED AT
THEM, AND WE LOOK AT THOSE IN
RELATION TO AMYLOID, AT TAU
WHICH ARE CANNONICLE ALZHEIMER'S
DISEASE AND THEN THE ACIDIC
PROTEIN WHICH IS A MARKER OF
REACTIVE NUCLEOSIS, SO SOME
INDICATE A TYPE OF NEURAL
INFLATION AND THE NEURAL LIGHT
WHICH IS A MEASURE OF AXONAL
DAMAGE WHICH IS NOT REALLY
DEMENTIA SPECIFIC BUT SENSITIVE
TO DISRUPTION AND NEURAL
FUNCTION OR NEURONAL INJURY, BUT
WE SAW AMONG OUR PROTECTIVE
PROTEINS AND EVERYTHING WITH THE
RED ARROW, IS LINKED TO
INFLUENZA, AND SOMEWHERE IN
HERE, BUT AMONG OUR PROTECTIVE
PROTEINS, WE SEE THAT THEY ALSO
SHOW THIS DOWN REGULATION, ARE
ASSOCIATED WITH DOWN REGULATION
OF P-TILE AND THIS UPREGULATION
OF THE 48-FROM--INTEGRATION
RATIO AND YOU CAN THINK OF IT IN
REVERSE, HIGH 48-40 MEANS LESS
CORTICALE AMYLOID, LESS AMYLOID
ON THE BRAIN SO THIS IS ALL
CONSISTENT WITH THE PICTURE OF
PROTECTION, IF WE ELECTRIC AT
OUR PATHOGENIC PROTEINS, WE
DON'T SEE A CONSISTENT PICTURE
IN TERMS OF THE MOLECULAR
PICTURE, SO A LOT OF STUFF THAT
WAS ASSOCIATED OR DEEMED
PATHOGENIC, IN RELATION TO
INFLUENZA AFFECT ON BRAIN
ATROPHY DIDN'T SO A RELATIONSHIP
WITH AMYLOID G OR TAU, IF SO
WE'RE STILL TRYING TO SHOW IF
THESE MECHANISMS ARE CAUSAL,
WHAT ARE THEIR EFFECTS?
SAME THING WITH SKIN, WE SAW 2
PATHEE GENIC, 1 PROTECTIVE AND
THESE ARE DISCORDANT, THEY'RE
UPREGULATIVE AND POST INFECTION
AND ALSO PROTECTIVE AND DIDN'T
KNOW WHAT TO MAKE OF THAT, WE
WERE ABLE TO TRY TO GET AT THE
CAUSAL QUESTION BY LOOKING AT
GENETIC OVERLAP, SO THIS MEN
DEALIAN RANDOMIZATION ANALYSIS,
SO WE DID A GWAS ON THE PROTEIN
LEVEL, WHERE WE MAY USE SOMEONE
ELSE'S QUANTITATIVE LOCI, I
FORGET BUT WE WERE ABLE TO LOOK
TO SEE IF THE PROTEIN
QUAWBTITATIVE TRAIT LOCI FOR
THESE INDIVIDUAL PROTEINS
OVERLAP WITH THE RISK VARIANCE
FOR ALZHEIMERAY DISEASE AND THAT
ALLOWS US TO BE--MAKE A STRONGER
CAUSAL INFERENCE AND FOR SOME OF
THE TEENS THAT WERE ACTUALLY
BEING IDENTIFIED AS RELEVANCE
AND SKIN AND CUE TAINIOUS
INFECTION, WE DID SEE EVIDENCE
FOR A CAUSALITY, THE OUTCOME
HERE BEING BRAIN ATROPHY SO BACK
TO OUR ORIGINAL MEASUREMENT OF
NEURODEGENERATION EMPLOY OKAY,
WE SAW THESE--WE SAW THE NUMBERS
THAT WERE ASSOCIATE WIDE
COGNITION AS WELL, IN THE SAME
COHORT, BUT I WANT TO, YOU KNOW
SPEND SOMETIME HERE BECAUSE THIS
IS 1 OF THE SUM RESULT OF OUR
ANALYSIS, WE TARTED WITH 7000
PROTEINS, HERE IN THE BLSA, AS
POTENTIAL CANDIDATES, WE FOCUSED
THEN DOWN ON 900 THAT WE KNOW
WHERE IMMUNE RELATED, SO WE LOOK
AT THOSE IMMUNE RELATED WITH A
HISTORY OF INFECTION AND FOUND
WHICH OF THOSE PROEN TOOS WERE
WITH INFECTION WERE ASSOCIATE
WIDE BRAIN ATROPHY, SO THROUGH
ALL THAT WE CAME DOWN ON THE
PROTEINS AS POTENTIAL MEDIATOR,
NOW THE FRAMEWORK WE HAVE NOW IS
THAT INFECTION, YOU KNOW, BOTH
INCREASES PATHOGENIC PROTEIN
EXPRESSION AND CIRCULATION,
DECREASES PROTECTIVE PROTEIN
EXPRESSION IN CIRCULATION, AND
FOR THESE PROTECTIVE PROTEINS,
WHICH ARE LABELED IN PINK DOWN
HERE SORRY LABELED IN PURPLE OR
BLUE OR WHATEVER THAT IS DOWN
HERE, FOR THESE PROTECTIVE
PROTEINS, WE SEE THAT THE
MOLECULAR CHANGES WHEN WE DOWN
REGULATE THEM, ARE THIS INCREASE
IN AMYLOID, INCREASE IF PTA, UU
AND WHICH ARE MONOMERIC OF
ALZHEIMER'S DISEASE AS WELL, SO
WE THINK THAT MIGHT BE WHAT'S
GOING OYOU HAVE A HISTORY OF
INFECTION, IT REDUCES THESE
IMMUNE PROTEINS THAT ARE
PROTECTIVE AND THAT LAYS THE
GLOWND WORK FOR THE P, TAU, AND
A HYPOTHESIS THAT MAY BE EQUALLY
OR MORE LIKELY IS THAT THERE'S
SOME COMMON IMMUNE TRAIT THAT
MAKES PEOPLE HAVE LOW LEVEL OF
THESE PROTECTIVE PROTEINS AND
MAKES SUSCEPTIBLE TO
NEURODEGENERATION.
SO YOU MAY BE BORN WITH THIS,
THIS IMMUNE TRAIT WHICH ACTUALLY
MAY BE PROTECTIVE IN EARLY LIFE
OR MAYBE MAKE YOU MORE OR LESS
SEZ SEPTORSIBLE TO CERTAIN
INFECTION EMPLOY BUT I GUESS IN
THIS CASE MORE SUSCEPTIBLE, AND
THOSE SEEMINGLY UNDERLYING
IMMUNE TRAITS IT MAY BE THAT YOU
DEVELOP ALZHEIMER'S DEC IN THE
FUTURE AND THESE PROTEINS,
PROTEOMIC EXPRESSIONS HERE MIGHT
JUST BE A SIGNATURE OF THAT
IMMUNE TRAIT.
WE'RE TRYING TO TEST THAT MORE
SPECIFICALLY NOW USING A NUMBER
OF METHODS AND THEN WE HAVE OUR
PATHOGENIC PROTEINS AND WE DON'T
KNOW WHAT THE MEDIAITOR IS HERE,
WE SEE THE PATHOGENIC, WE SEE
THEM ASSOCIATED AND UPREGULATED
POST INFECTION BUT THEY'RE NOT
ASSOCIATED WITH AMYLOID AND TAU,
SO THERE'S STILL WORK TO BE DONE
TO SORT OF COMPLETE THE PICTURE,
THERE MAY BE JUST A DIRECT
RELATIONSHIP.
SO JUST TO SUMMARIZE, WHEN WE DO
THINK WITH THE KEY INFLAMMATORY
EVENTS THERE'S THIS UPREGULATION
IN PURPLE MEDIATORS, THAT CAN
GET INTO THE BRAIN OR SIGNAL TO
THE BRAIN AND ACTUALLY YOU KNOW
DISREGULATION AMYLOID OR TAU AND
MAKE THEM MORE SUSCEPTIBLE TO
NEURODEGENERATION THAT MAY HAVE
NOT OCCURRED.
I WOULDN'T GO AS WISE AS SAYING
INFECTION, I WILL SAY TRIGGERS
DEMENTIA BUT WE DO HAVE EVIDENCE
HERE THAT IT CAN BE A RISK
FACTOR.
SO I'LL STOP THERE, THANKS
EVERYONE FOR LISTENING AND I'M
HAPPY TO TAKE QUESTIONS BUT
BEFORE THAT I WANT TO THANK THE
FOLKS IN MY LAB, PARTICULARLY
THOSE WHO WORK I REFERENCED HERE
AND THEN THE ARIC COLLABORATORS
AS WELL AND THE FOLKS THAT WORK
AT STUDIES OF MULTIPLE
ENDOCRINIA LOGIC.
THANKS FOR LISTENING AND I HOPE
YOU HAVE QUESTIONS.
>> WE HAVE 1 QUESTION FROM ZOOM,
WHAT IS THE EFFECT OF AGEOT
ASSOCIATIONS BETWEEN INFECTIONS
AND THE AD BIOMARKERS IN.
>> WE DIDN'T LOOK AT AGE AS A
MODIFIER OF THOSE RELATIONSHIPS
SPECIFICALLY, LET ME THINK ABOUT
THAT.
SO, YEAH, I MEAN THE SHORT
ANSWER IS QUEE DON'T KNOW.
IT SEEMS LIKE AGE MAKES THE
INFECTION ITSELF A STRONGER RISK
FACTOR FOR NEURODEGENERATION,
INFECTIONS IN THE COVID TABLE,
WE DIDN'T TEST THE INTERACTIONS
IN THE LAST PAPER I SHOWED BUT
IF YOU HAVE A SEVERE INFECTION
AND YOU'RE 70, IT SEEMS TO BE A
LOT MORE ON DEMENTIA RISK THAN
IF YOU HAVE A SEVERE INFECTION
IN THE LIFE, NOW HOW THAT
AFFECTS ERD BIOMARKERS, YOU KNOW
I ASSUME, YOU KNOW WE WOULD SEE
A SIMILAR PATTERN WHERE
INFECTIONS HAVING A STRONGER
EFFECT ON THOSE BIOMARKERS AT A
LATER LIFE THAN EARLIER IN LIFE
BUT WE DIDN'T TEST THAT
DIRECTLY.
>> I HAVE A QUESTION, SO WHEN
YOU DID THIS INFECTION
CORRELATION, DID YOU LOOK AT THE
SIGNATURE PROTEIN YOU FOUND IN
THE OTHER STUDY?
DO THEY ALSO CORRELATE IN THIS?
>> IN THE OTHER STUDY?
>> IN THE EARLIER STUDY WHERE
YOU LOOK AT AGE RELATED.
>> YEAH, SO WE TOOK THE
INFECTION PROTEIN, PARTICULARLY
OUR CANDIDATES THAT WE
HIGHLIGHTED HERE AND THEN WE DID
ACTUALLY TAKE THEM BACK TO THE
FIRST I MENTIONED THE ARIC STUDY
IF THEY WERE THE DEMENTIA RISK
AND SO THAT IS SOMETHING WE DID
SOME OF THEM, CERTAINLY NOT ALL
OF THEM, IT MAY HAVE BEEN LIKE A
THIRD THAT WERE SOABT WIDE
DEMENTIA EITHER IN THE FUTURE,
OR WERE ELEVATED IN PEOPLE WHO
CURRENTLY HAD DEMENTIA VERSUS
THOSE THAT WE DID AND IT WAS
LESS THAN WE ANTICIPATED AND YOU
KNOW WE WEREN'T SURE NECESSARILY
WHY.
>> I WAS THINKING THE OTHER WAY
AROUND LIKE LOOKING AT THE
[INDISCERNIBLE] YOU PREDICTED IN
THE AGE RELATED STUDY ANDEE IF
THEY WERE ACTUALLY CORRELATED
HERE WITH THE [INDISCERNIBLE].
>> OH, NO, WE DIDN'T DO THAT.
WE TRIED TO NARROW THEM MPLE SO
--NARROW
THEM.
SO PART OF THE STUDY I MENTIONED
WE DIDN'T NARROW THE SCOPE TO
OUR IMMUNE RELATED PROTEIN SO
SOME OF THE INITIAL PROTEIN FROM
THE INITIAL SET OF ANALYSIS,
IMMUNE RELATED BUT I WOULD SAY
MAYBE A FOURTH OF THEM WERE
INVOLVED IN OTHER YOU KNOW
ASPECTS OF BIOLOGY.
>> THANKS.
>> THANK YOU FOR A NICE TALK.
I HAVE A QUESTION ABOUT THE DATA
PROCESSING, WHENEVER I SAW YOUR
DATA, THERE WAS 1 SENTENCE WHERE
THE RESULTS ARE JUST FOR THE
AGING [INDISCERNIBLE] AND I SAW
THE SAMPLE NUMBERS REALLY
GIGANTIC, I FEEL LIKE
[INDISCERNIBLE] PROCESS AND HOW
DID YOU DO IT FOR THE
ASSESSMENT?
>> I MISSED THE LAST SENTENCE?
>> HOW DID YOU DO THE ADJUSTMENT
FOR THE MRI ANALYSIS OR DEMENTIA
ANALYSIS OR BOTH?
>> THE LAST PART OF YOUR DATA.
>> YEAH, SO THE ADJUSTMENT SO
THIS SORT OF STUFF AND TRY TO
TAKE INTO ACCOUNT AGE AS BASED
DEMENTIA RISK FACTOR AND
SOMETHING THAT OBVIOUSLY
INFLUENCES PROTEOME, AND WE
TYPICALLY AJUST FOR THAT AND
IT'S A BIT AS A CONFOUNDER, WE
DO SETS, DO DEMOGRAPHIC FACTORS,
AND THIS MIGHT BE LITTLE--WE
CHANGE IT DEPENDING ON OUR
HYPOTHESIS BUT WE TYPICALLY WILL
JUST HAVE A COMMENT, CO VASCULAR
MORBIDITY THAT ARE THINGS AGAIN
THAT WE KNOW MAY NEED THE RISK
FACTORS THEMSELVES, AND THINGS
LIKE HYPERTENSION,
CARDIOVASCULAR DISEASE, AND
METABOLIC CONDITIONS LIKE
DIABETES.
THOSE SEEM TO MAKE IT INTO THE
MODEL.
AND THEN THE OTHER THING THAT
WE--THIS IS SOMEWHAT
CONTROVERSIAL IS KIDNEY
FUNCTION, WE OFTEN ADJUST FOR
THAT, IT MAY NOT BE REPRESENTED
HERE BUT WE KIND OF THINK KIDNEY
FUNCTION IN OLDER ADULLS SEEMS
TO INFLUENCE A LARGE SEGMENT OF
THE PROTEOME ITSELF.
AND DESCENT SIZE CHAIMPLES IN
THE RELATIONSHIP BETWEEN YOU
KNOW PROTEINS AND VARIOUS
OUTCOMES.
BUT WHAT THAT DOES ON THE FLIP
SIDE IS WE THINK THERE'S A
PROTEIN THAT IS ACTUALLY
RELEVANT TO OUR OUTCOME, LIKE
THE BETA 2 MICROGLOBUE LYNN, YOU
KNOW WE DON'T GET TO SEE THAT
ASSOCIATION BECAUSE WE ARE
TRYING TO GET RID OF THE
CONFOUNDING [INDISCERNIBLE]
REDUCE LOW FOR THE KIDNEY SO
THAT'S SOMETHING THAT WE DO BUT
NOT EVERYONE DOES BUT HA CAN BE
ADJUSTMENT AND WE WILL SOMETIMES
ADJUST FOR APO-E AS A MAJOR RISK
FACTOR.
>> THANK YOU.
>> YEAH?
>> DIRECTLY CORRELATED WITH
INCREASED RISK?
>> YEAH, WE DID, LIKE HAVING A
HISTORY OF 2 OR 3, YEAH, WE DID
LOOK AT STEP WIDE ASSOCIATIONS,
WE DIDN'T SEE MUCH IN OUR
ANALYSIS BUT I KNOW OTHER PEOPLE
HAVE, AND YOU KNOW WHETHER IT BE
THE DIVERSITY, IS IT MORE
PROBLEMATIC TO HAVE THE FLU HHV,
AND URI, VERSUS LIKE THE FLU 3
TIMES.
SO PEOPLE LOOK AT IT BOTH WAYS
AND THERE DOES TEND TO BE A STEP
WISE, MEAN IN THE EPIDEMIOLOGIC
WORK THIS DID SEEM TO BE
[INDISCERNIBLE] FACT.
BUT I DO THINK, WE KNOW THERE'S
PEOPLE OUT THERE WHO ARE JUST
SEEM TO ARE MORE SUSCEPTIBLE TO
THESE INFECTIONS AND I WONDER IF
A HYPOTHESIS IS SOME OF THESE
GENERATED ELTICS MAY MAKE THEM
MORE SUSCEPTIBLE TO THE
INFECTION WHICH MAY ALSO MAKE
THEM MORE SUSCEPTIBLE TO THE
BRAIN OR CAN'T CLEAR AS WELL OR
EFFICIENTLY SO THERE MAY BE AN
UNDERLYING IMMUNE TRAIT THAT
CONTRIBUTES TO THAT CONDITION
AND FROM THAT YOU WOULD SEE THE
STEP WISE RELATIONSHIP, I THINK.
NFOLKS, IF NO MORE QUESTIONS,
LET'S THANK DR. WALKER FOR
COMING OUT HERE TO GIVE THE
TALK.
[ APPLAUSE ]
>> THANKS FOR HAVING ME.