GOOD AFTERNOON, EVERYBODY.
WELCOME TO THE FIRST DIRECTOR'S
SEMINAR OF 2025.
HAPPY NEW YEAR, EVERYBODY HERE
IN THE AUDIENCE, AND EVERYONE
ONLINE ON VIDEOCAST.
IT'S A REAL PLEASURE ALWAYS TO
INTRODUCE THE SPEAKER FOR THE
DIRECTOR'S SEMINAR SERIES, WHICH
PRESENTS NEWLY TENURED
INVESTIGATORS AT NIH, AND OUR
SPEAKER TODAY IS DR. SONJA
SCHOLZ FROM NINDS, WHO GOT HER
MEDICAL DEGREE AT MEDICAL
UNIVERSITY IN AUSTRIA AND WENT
ON TO DO A Ph.D. AT UNIVERSITY
COLLEGE LONDON.
SHE DID HER Ph.D. IN
NEUROGENOMICS AND THEN DID A
POSTDOCTORAL FELLOWSHIP FIRST AT
GEORGETOWN UNIVERSITY, AND THEN
HERE AT NIH AT THE NATIONAL
INSTITUTE ON AGING, WITH ANDY
SINGLETON.
AND REALLY THAT SET THE STAGE
FOR THE WORK THAT SHE'S DONE AS
AN INDEPENDENT INVESTIGATOR.
SHE BECAME A TENURE TRACK
INVESTIGATOR IN THE LASKER
CLINICAL RESEARCH SCHOLARS
PROGRAM, AND LAUNCHED HER
LABORATORY IN NEURODEGENERATIVE
DISEASE RESEARCH.
JUST LAST YEAR WAS GRANTED
TENURE AND BECAME A SENIOR
INVESTIGATOR.
ALL OF THAT IS THE SORT OF
TANGIBLE DATA, THE STUFF YOU PUT
IN A SPREADSHEET, BUT I WILL
TELL YOU FOR ME AS A
NEUROLOGIST, A NEUROSCIENTIST,
REALLY THE SALIENT IMPORTANCE OF
SONJA'S WORK HAS BEEN SHE
SHIFTED THE PARADIGM THE WAY WE
THINK ABOUT NEURODEGENERATIVE
DISEASES.
SHE HAS TAUGHT US THESE DISEASES
MAY OUGHT BEST NOT THOUGHT OF AS
DISCRETE CLINICAL ENTITIES,
ALZHEIMER'S DISEASE, PARKINSON'S
DISEASE, HUNTINGTON'S DISEASE,
BUT RATHER ASSORTMENTS,
DIFFERENT ASSORTMENTS OF, OF
DEEP PHENOTYPIC CHARACTERISTICS
THAT CO-SEGREGATE WITH
ASSORTMENTS, AGAIN, OF GENOMIC
ABNORMALITIES.
SO THAT MOST OF THE PATIENTS
WITH ANY OF THESE DISORDERS THAT
INVOLVE AGGREGATION OF LARGE
PROTEINS IN THE CENTRAL NERVOUS
SYSTEM REALLY ARE SOMEWHERE IN
THE CRACKS BETWEEN THE DISCRETE
ENTITIES THAT HAVE BEEN
CHARACTERIZED OVER THE YEARS.
AND SO SONJA 'S TALK TODAY, WHIH
I ALREADY MESSED UP BY HITTING
SOME BUTTONS ON THIS -- LET ME
JUST TRY TO GET THIS BACK FOR
YOU.
SORRY ABOUT THAT.
THERE WE GO.
EXCELLENT.
SONJA'S TALK TODAY IS
"UNLEACH LEASHING POTENTIAL OF
GENOMICS WITH LEWY BODY DEMENTIA
AND RELATED DISEASES."
CONGRATULATIONS FROM ALL OF US
AND WELCOME.
[APPLAUSE]
>> GOOD AFTERNOON, EVERYBODY.
THANK YOU, DR. SCHOR, FOR THE
KIND INTRODUCTION AND
OPPORTUNITY TO SPEAK TO YOU
TODAY, ALSO THANK YOU TO THE
PEOPLE IN THE ROOM BRAVING THE
COLD TEMPERATURES TODAY TO COME
HERE.
I'M GOING TO TALK TODAY ABOUT MY
RECENT LAB'S RESEARCH EFFORTS
TRYING TO USE MODERN GENOMICS
TOOLS TO UNDERSTAND COMPLEX
NEURODEGENERATIVE DISEASE.
LEWY BODY IS THE TEMPLATE, THE
MODEL THESE DAYS, BUT WHAT IS
HAPPENING IS GOING ON IN OTHER
DISEASES AS WELL.
THERE'S HOPE TO BE OPTIMISTIC
ABOUT THE FIELD.
HERE ARE MY DISCLOSURES.
SO THE MAIN ISSUES THAT I WANTED
TO DISCUSS TODAY IS I WANT TO
BASICALLY HIGHLIGHT, YOU KNOW,
RECENT GENOMIC ADVANCES, AND HOW
THESE GENOMIC ADVANCES ARE
REALLY STARTING TO PAVE THE WAY
FOR PRECISION MEDICINE,
PRECISION NEUROLOGY
INTERVENTIONS.
MOLECULAR INSIGHTS WE'VE GAINED
IN LEWY BODY DEMENTIA
SPECIFICALLY, BUT I WANT TO
HIGHLIGHT HOW THIS KNOWLEDGE CAN
BE SEEN, HOW DO THEY RELATE TO
OTHER DISEASES.
AND THEN FROM THAT I WILL
OUTLINE HOW WE CAN BEST USE THAT
KNOWLEDGE IN THE CLINICAL
CONTEXT TO BETTER DIAGNOSE,
SUBSTRATIFY, ULTIMATELY TREAT
THESE CHALLENGING CONDITIONS.
AND SO I'M GOING TO GIVE
BACKGROUND.
I THINK IT'S FAIR TO SAY WE'RE
LIVING IN A REALLY EXCITING
TIME, SINCE THE FIRST DRAFT OF
THE HUMAN GENOME HAS BEEN
PUBLISHED IN THE EARLY 2000s,
THERE HAS BEEN JUST A REVOLUTION
OF GENOME INSIGHTS AND
GENOMICALLY BASED TREATMENTS
THAT ARE COMING TO THE PATIENTS.
THESE ARE DISEASES THAT SUCH AS
SPINAL MUSCULAR ATROPHY, LOU
GEHRIG'S DISEASE, RARE UNUSUAL
DISEASES.
WHEN I TRAINED AS A PHYSICIAN I
HONESTLY THOUGHT THAT TREATMENTS
FOR THOSE DISEASES IS KIND OF
SCIENCE FICTION.
THIS IS ALREADY REALITY.
SO THERE'S A LOT MORE HAPPENING
NOW IN THE PRE-CLINICAL SPACE.
AND FOR THE MOST PART WHAT'S
COMING TO THE FOREFRONT ARE, YOU
KNOW, THERAPIES FOR SO-CALLED
MONOGENIC DISEASES WHERE YOU
HAVE ONE MAJOR GENETIC DEFECT
THAT EITHER CAUSES LOSS OF
FUNCTION OR TOXIC GAIN OF
FUNCTION AND USING THE VARIOUS
STRATEGIES SUCH AS GENE
REPLACEMENT WITH AAV VECTORS OR
GENE TARGETED USING ASOs, OR
GENE EDITING WHICH LOOKS VERY
PROMISING, THESE ARE THE DISEASE
WHERE IS WE HEAR A LOT NOW
COMING INTO THE FDA PIPELINE.
BUT OUR STORY DOESN'T STOP
THERE.
FOR THE MOST PART, THE PATIENTS
THAT I SEE IN THE CLINIC, THOSE
ARE PATIENTS WHO HAVE ADULT
ONSET APPARENTLY SPORADIC
CONDITIONS.
AND SO, THE GENETIC STILL PLAYS
A ROLE IN THOSE DISEASES
ALTHOUGH IT'S MORE COMPLICATE.
CONCEPTUALLY WE THINK ABOUT A
LOT OF ADULT ONSET DISEASES AS
POLYGENIC WHERE YOU HAVE RISK
GENES THAT ARE COMING TOGETHER
AND THAT IN AGGREGATE CAN DRIVE
DISEASE, MAY NOT ALWAYS BE
ENOUGH TO CAUSE IT BUT STILL CAN
GIVE US A LOT OF INFORMATION
ABOUT THE UNDERLYING
PATHOPHYSIOLOGY, AND CAN ALSO
REALLY HELP US DEVICE NEW
TREATMENT STRATEGIES.
SO FOR EXAMPLE BY IDENTIFYING
CAUSAL RELATIONSHIP WITH OTHER
DISEASES WE MAY BE ABLE TO
REPURPOSE CERTAIN DRUGS THAT
HAVE BEEN DEVELOPED, ONE DISEASE
FOR ANOTHER.
AND WE ALSO CAN REALLY IDENTIFY
WHERE ARE THE PATHWAYS TO
IMPORTANT NOTES WITHIN CELLULAR
NETWORKS THAT SEEM TO BE ALWAYS
DYSFUNCTIONAL.
THOSE ARE THE ONES WE WANT TO GO
AFTER FROM A THERAPEUTIC
TRANSLATIONAL POINT OF VIEW.
AND SO, THE MAIN KIND OF TOOLS
WE'RE USING AS GENETICISTS ARE
SEGREGATION ANALYSIS WHICH IS
ESSENTIALLY WHAT WE'VE BEEN
USING FOR A LONG TIME WHEN WE
LOOK AT MENDELIAN DISEASES BUT
NOWADAYS IT'S REALLY, YOU KNOW,
A NUMBERS GAME WITH MODERN
GENOMIC TOOLS, COMPUTATIONAL
CAPABILITIES, ESSENTIALLY DOING
ASSOCIATION TESTS.
WE COMPARE LARGE CORDS OF CASES
VERSUS CONTROLS AND TRY TO MAP
OUT THAT PLOT WHERE WE
ESSENTIALLY MAP OUT RISK GENES,
HIGH IMPACT VERSUS LOWER IMPACT,
AND EACH ONE OF THOSE CAN TELL
US SOMETHING ABOUT THE
UNDERLYING PATHOPHYSIOLOGY.
OUR JOB DOESN'T STOP THERE.
ONCE WE PINPOINT THERE'S
SOMETHING IN THE GENOME THAT'S
ASSOCIATED WITH OUR DISEASE OF
INTEREST, WE CAN NOW USE MAPS
ARE OR CATALOGS OF OTHER OMIC
DATA, FOR EXAMPLE TRANSCRIPTION
DATA, TO LOOK AT WHAT IS THE
MOST LIKELY UNDERLYING GENE
WITHIN THE LOCUS OF INTEREST AND
WHAT'S IN SOME INSTANCES COULD
BE THE POTENTIAL MECHANISM.
IS IT A LOSS OF FUNCTION, IS IT
AN INCREASE IN EXPRESSION, ET
CETERA, SO WE'RE USING
INCREASINGLY JUST BY
COMPUTATIONAL MODELING A SYSTEMS
BIOLOGY FRAMEWORK.
AND WITHOUT EVEN HAVING TOUCHED
AN ANIMAL MODEL OR CELL MODEL.
THAT REALLY ACCELERATES OUR
ABILITY TO BOIL DOWN TO THE MOST
IMPORTANT MOLECULAR DEFECT.
BUT THE OTHER THING THAT'S
ACTUALLY QUITE ELEGANT IS WE CAN
ALSO LEVERAGE GENOMIC TOOLS TO
MAKE CAUSAL INFERENCES, NOT JUST
USING ASSOCIATION TESTS BUT
GENUINELY TELL US IF WE CAN TELL
SOMETHING ABOUT A CAUSAL
RELATIONSHIP, USING MODERN
COMPUTATIONAL TOOLS SUCH AS
MENDELIAN RANDOMIZATION STUDIES.
I'LL SHOW EXAMPLES HOW WE
LEVERAGED SOME OF THESE TOOLS
THERE ARE.
THERE'S A GROUP OF DISEASES THAT
FALLS UNDER THE UMBRELLA OF
ATYPICAL PARKINSON SYNDROME,
UNDERSTUDIED NEURODEGENERATIVE
DISEASE, ONE IS LEWY BODY
DEMENTIA, WE SEE ABNORMAL
DEPOSITION OF A PROTEIN CALLED
ALPHA SIGH
ALPHA-SYNUCLEIN.
WHAT MAKES IT CHALLENGES IS
CLINICAL VARIATIONS CAN BE
VARIABLE EARLY ON, AS A
CONSEQUENCE PATIENTS ARE OFTEN
NOT RECOGNIZED UNTIL MUCH, MUCH
FURTHER ALONG WHEN THEY ARE
ALREADY QUITE DISABLED AND
DEVASTATED BY THE CONDITION.
TO BE EFFECTIVE, GENOMIC
STUDIES, WE NEED LARGE COHORTS,
THAT CAN BE DIFFICULT TO
RECRUIT.
BUT I WOULD ARGUE BEING AT THE
NIH INTRAMURAL RESEARCH PROGRAM
WHERE WE HAVE A MORE STABLE
FUNDING ENVIRONMENT IT'S
ACTUALLY A REAL IDEAL SCENARIO
WHERE WE CAN BRING RESOURCES TO
BEAR BOTH AT THIS LARGE TEAM
SCIENCE EFFORT.
THERE'S ALSO LACK OF PUBLIC
GENOMIC RESOURCES, SOMETHING
THAT WE'RE REALLY TRYING TO
REMEDY AS MUCH AS POSSIBLE BY
MAKING DATA RAPIDLY AVAILABLE TO
ACCELERATE DISCOVERIES IN THESE
UNDERSTUDIED DISEASES.
AND HOPEFULLY HOPEFULLY EFFECT,
SOME CHANGE.
WE'RE GOING TO TALK MORE ABOUT
LEWY BODY DEMENTIA, AN AREA OF
INTEREST.
LEWY BODY DEMENTIA, MANY OF YOU
KNOW, IS AN ADULT ONSET
DEVASTATING NEURODEGENERATIVE
DISEASE, CHARACTERIZED BY
COMPLEX CLINICAL FEATURES THAT
INCLUDE PARKINSONISM, VISUAL
HALLUCINATION, SLEEP DISORDERS,
FLUCTUATIONS IN ATTENTION, ALSO
AUTONOMIC NERVOUS SYSTEM
INVOLVEMENT.
IT VARIES FROM PERSON TO PERSON.
WE'VE LEARNED THAT THESE
PATIENTS HAVE ABNORMAL
DEPOSITION OF THE
ALPHA-SYNUCLEIN PROTEINS, IN THE
FORM OF LEWY BODYs.
60 TO 80%, THERE'S ALZHEIMER'S
DISEASE CO-PATHOLOGY, FORM OF
AMYLOID PLAQUE, AND
NEUROFIBRILLARY TANGLES.
WE'VE INCREASINGLY APPRECIATED
THAT THERE IS A SUBSET OF
PATIENTS THAT CLEARLY HAVE A
FAMILY HISTORY.
AND THERE SEEMS TO BE A GENETIC
PREDISPOSITION, AT LEAST IN
THOSE INDIVIDUALS THAT HAVE A
FAMILY HISTORY, BUT EVEN IN
THOSE THAT APPARENTLY SPORADIC,
SO MAYBE ADDITIONAL GENETIC
FACTORS THAT COULD PLAY A ROLE,
IT'S AN AGED POPULATION, WE
DIDN'T LIVE AS LONG, ANCESTORS
DIDN'T SURVIVE AS LONG IN THE
PAST.
LEWY BODY IS PERCEIVED AS RARE
BUT IT'S ACTUALLY THE SECOND
MOST COMMON NEURODEGENERATIVE
DEMENTIA AFTER ALZHEIMER'S,
1.4 MILLION PEOPLE IN THE UNITED
STATES ALONE, ABOUT 5% OF ALL
DEMENTIA CASES, BUT MORE
ESPECIALLY THE ONES THAT OVERLAP
WITH ALZHEIMER'S DISEASE.
AND BECAUSE WE HAVE THESE
COMPLEX MOTOR AND NON-MOTOR
FEATURES, IT IS A REALLY
DEVASTATING DISEASE TO DEAL
WITH.
IT HAS HIGHEST COST OF ALL
DEMENTIAS ASSOCIATED WITH IT.
SO THERE'S A LOT OF NEED TO
IMPROVE OUR UNDERSTANDING SO WE
CAN DEVELOP TREATMENTS TO SLOW
DOWN THE DISEASE PROCESS.
AND SO THERE'S BEEN, YOU KNOW, A
FAIR AMOUNT OF, YOU KNOW,
OBSERVATIONAL STUDIES ALREADY
THAT HAVE IMPLICATED THAT
GENETICS IS PLAYING A ROLE.
I MENTIONED FAMILY HISTORIES
THAT HAVE BEEN OBSERVED.
THEY ARE SUSPICIOUS.
WE'VE SEEN SEVERAL FAMILIAL
CASES AT THE NIH AS WELL.
WE'VE NOTICED SIBLINGS OFTEN
HAVE INCREASED RISK OF LEWY BODY
DEMENTIA, ALSO INDICATIVE OF A
HERITABLE CONTRIBUTION.
AND THERE'S HERITABILITY WE CAN
ESTIMATE BASED ON COMMON GENETIC
VARIANTS.
THERE MAY BE INTERESTING SEX
DIFFERENCES.
WE DEFINITELY SEE MEN MORE
COMMONLY WITH THIS CONDITION
THAN WOMEN.
AND WHILE I -- YOU KNOW, I FOCUS
IN ON THE GENETICS, IT DOESN'T
MEAN GENETICS IS THE ANSWER TO
EVERYTHING.
IT'S AGE-RELATED DISEASE,
THERE'S AGING, ENVIRONMENTAL
FACTORS, THERE'S EPIGENETIC
CHANGES, LIFESTYLE CHANGES THAT
PROBABLY COME TOGETHER BUT THE
LEAST GENETICS IS SOMETHING VERY
TRACTABLE THAT WE CAN TEASE
APART USING MODERN TECHNOLOGIES.
AND SO VERY BRIEFLY LOOKING AT
THE HISTORY OF LEWY BODY
DEMENTIA, GENETICS, IT'S A
RELATIVELY YOUNG FIELD, THREE
DECADES SINCE WE OPERATIONALIZED
THE CRITERIA FOR LEWY BODY
DEMENTIA.
AND THE FIRST COUPLE YEARS
REALLY CONSISTED OF CANDIDATE
GENE STUDIES, IN THIS CASE QUITE
SUCCESSFUL.
SO PARKINSON'S DISEASE AND
ALZHEIMER'S DISEASE FIELD,
INSIGHT ALLOWED CANDIDATE GENE
STUDIES ON LEWY BODY DEMENTIA.
SEVERAL GENES HAVE BEEN
CONFIRMED AS BEING IMPORTANT IN
LEWY BODY.
IT WASN'T UNTIL IT CAME TO THE
FOREFRONT WE'VE BEEN ABLE TO
LOOK INTO THE BROADER SPORADIC
FORMS OF LEWY BODY DEMENTIA, AND
THIS IS WHAT I'M GOING TO SHOW
YOU TODAY.
SO ONE OF THE VERY FIRST
PROJECTS CONSISTED OF EXOME
SEQUENCING OF A PATHOLOGICALLY
CONFIRMED COHORT.
AND THIS WAS DRAWN FROM THE
HOPKINS BRAIN BANK.
WE WERE JUST ASTONISHED TO SEE
ABOUT 25% OF ALL PATIENTS
ACTUALLY HAD HIGH RISK OF
PATHOGENIC MUTATION.
IN ONE OF THOSE, THE THREE
GENES, THOSE ARE IMPORTANT RISK
GENES.
WE HAD DIFFICULTY PUBLISHING
BECAUSE NOBODY BELIEVED THAT IT
WAS -- THAT THAT'S THE CASE,
WE'RE SPOT ON.
WE NOTICED APOE 4 PLAYS A ROLE,
DEMONSTRATED THAT AND CLEARLY
HAD MAJOR EFFECT ALSO ON
SURVIVAL.
WE COLLABORATED WITH
INTERNATIONAL TEAM, FIRST GENOME
WIDE ASSOCIATION STUDY, AGAIN
CONFIRMING GENES THAT HAVE BEEN
PREVIOUSLY IMPLICATED BASED ON
CANDIDATE GENE WORK, GBA, SNCA,
APOE AS IMPORTANT IN THE PATIENT
POPULATION.
WE REALIZED ONLY A SMALL
FRACTION OF THE HERITABILITY
THAT EXISTS COULD BE EXPLAINED
AT THAT TIME.
SO THAT WAS REALLY THE MAIN
IMPETUS FOR US TO LAUNCH A
GENOME SEQUENCING INITIATIVE.
THIS WAS FUNDED THROUGH THE
NATIONAL INSTITUTE ON AGING, SO
A LARGE DEMENTIA GRANT.
AND WE BASICALLY WENT THROUGH
EVERY BRAIN BANK WE COULD
IDENTIFY, ANYBODY WHO WAS
WORKING IN THE FIELD, TO
ASSEMBLE A COHORT OF 2600 CASES,
AND ABOUT 4,000 NEUROLOGICALLY
HEALTHY CONTROLS.
OVER 2/3 WERE PATHOLOGICALLY
CONFIRMED AND PERFORMED WHOLE
GENOME SEQUENCING ON THEM USING
A UNIFORM PIPELINE FOR SAMPLE
PREPARATION SEQUENCING, AND
ALIGNMENT, JOINT VARIANT,
GENERALLY FOUNDATIONAL RESOURCE.
ALL DATA WENT PUBLIC BEFORE WE
HAD THE ANALYSIS OF THOSE DONE.
THIS WAS SLIGHTLY STRESSFUL FOR
ME AS A TENURE TRACKER, BUT WE
WERE PLEASED THAT, YOU KNOW,
EVERYTHING WAS REALLY WELL
RECEIVED.
WE SUBSEQUENTLY WERE ABLE TO
PUBLISH SOME INTERESTING
FINDINGS ON THAT.
AND SO HERE IS A GENOME WIDE
ASSOCIATION STUDY BASED ON OUR
WHOLE GENOME SEQUENCING DATA,
WHICH IMPLICATED FIVE GENOME
WIDE SIGNIFICANT RISK LOCI
INCLUDING GBA, SNCA, APOE, AND
TWO OTHERS BN 1, AND 75 IS AN
IMPORTANT RISK GENE IN
PARKINSON'S DISEASE.
LEWY BODY DEMENTIA GENETICALLY
SPEAKING SEEMS TO SIT ALONG THE
SPECTRUM BETWEEN PARKINSON'S
DISEASE ON ONE HAND, ALZHEIMER'S
DISEASE ON THE OTHER HAND.
BUT WHEN WE DID SOME MORE FINE
MAPPING OF SPECIFIC LOCI WE
COULD APPRECIATE THERE WERE
SUBTLE DIFFERENCES.
FOR EXAMPLE, AT THE SNCA LOCUS,
WHICH ENCLOUDS ALPHA-SYNUCLEIN
PROTEIN THAT'S DEPOSITED IN
THOSE LEWY BODIES, WE NOTICED
OUR INDEX VARIANT IS AT THE FIVE
PRIME END, WHICH OVERLAPS
NON-CODING TRANSCRIPT,
PARKINSON'S DISEASE THE MAIN
SIGNAL WAS IN THE INTRONIC
SEQUENCE, SO WHEN WE DID
ADDITIONAL FUNCTIONAL GENOMIC
MAPPING, WE COULD REALLY
DEMONSTRATE THROUGH
CO-LOCALIZATION ANALYSIS THAT
THERE IS -- THAT INCREASED RISK
OF SNCA-AS1 TRANSCRIPT THAT
NATURALLY LOWERS EXPRESSION OF
ALPHA
ALPHA-SYNUCLEIN IS PROTECTIVE
AND NEURONALLY SPECIFIC, AND
FITS WITH THE MODEL THAT TOO
HIGH EXPRESSION OF
ALPHA-SYNUCLEIN IS TOXIC, EVEN
AT MODEST LEVELS AS WE'RE SEEING
HERE WITH THE LEWY BODY DEMENTIA
GWAS.
AND AS A CONSEQUENCE BECAUSE
IT'S SUCH AN ATTRACTIVE TARGET
THERE'S ALSO -- THERE ARE
RESEARCH EFFORTS TO USE IT AS
POTENTIAL THERAPEUTIC TARGET FOR
THERAPY DEVELOPMENT.
WE HAVE GENOME SEQUENCE DATA.
AND THIS IS INCREDIBLY RICH.
SO WE CAN LOOK AT COMMON
VARIANTS, ALSO LOOK AT RARE
VARIANTS.
AND ONE OF THE GENES THAT WE
NOTICED WHERE WE HAD SIGNIFICANT
ENRICHMENT OF MUTATIONS WAS GBA,
ENCODES A GENE THAT HAS
PREVIOUSLY BEEN IMPLICATED IN
LEWY BODY DEMENTIA.
WE WERE ABLE TO REALLY SHOW THAT
A PATIENT WITH LEWY BODY
DEMENTIA VERY COMMONLY VARY
VARIANTS OR MUTATIONS IN THAT
GENE.
IF WE SUM UP COMMON AND RARE
VARIANTS THAT ARE PRESENT IN
LEWY BODY DEMENTIA, IT'S ABOUT
13% OF ALL PATIENTS.
AND THAT MAKES THE REALLY
INTERESTING PRIME TARGET ALSO
FOR THERAPY DEVELOPMENT, USING
CHAPERONES, SMALL MOLECULES, AND
IN PARTICULAR HERE, MIH, ELLEN
AT NHGRI HAS BEEN DIVERSITY IN
THIS FIELD.
WE MAY HEAR MORE ABOUT IT.
AND BECAUSE IT IS AN IMPORTANT
RISK GENE FOR PARKINSON'S
DISEASE COULD BE RELEVANT FOR
OTHER SPECTRUM OF PATIENTS
SUFFERING FROM NEURODEGENERATIVE
DISEASES.
, YOU KNOW, WE CAN TAKE A MORE
GLOBAL VIEW, CONSTRUCT CO-CALLED
POLYGENIC RISK SCORES AND TRY TO
LOOK AT THE RELATIONSHIP OF ONE
DISEASE VERSUS ANOTHER.
ON AVERAGE, USING GENETIC RISK
SCORE FOR ALZHEIMER'S DISEASE,
PARKINSON'S DISEASE, COMPARED TO
LEWY BODY DEMENTIA CAN PROVE
THERE'S OVERLAP IN GENETIC
ARCHITECTURE.
HIGHER RISK, REMAINS SIGNIFICANT
IF YOU REMOVE HIGHEST RISK LOCI
FOR EXAMPLE APOE, VARIANTS HAVE
BEEN DESCRIBED IN OTHER RELATED
NEURODEGENERATIVE DISEASES
PROBABLY ALSO PLAYING A ROLE AND
WE CAN ALREADY START TO
APPRECIATE ENRICHMENT OF
PATHWAYS THAT ARE CRUCIAL,
RELEVANT FOR PROTEIN
DEGRADATION, HANDLING.
MOVING ON WE ALSO HAVE NOVEL
WAYS OF LOOKING AT GENETIC
INFORMATION.
AND SO WE CAN LOOK AT VARIATIONS
THAT ARE USUALLY NOT EASY TO
CAPTURE, ONE CLASS IS SO-CALLED
STRUCTURAL VARIANTS.
THESE ARE BIGGER CHUNKS OF THE
GENOME EITHER DUPLICATED,
TRANSFERRED, INVERTED.
THERE'S A REASON TO FOCUS ON THE
VARIANTS, NOT ONLY AN IMPORTANT
SOURCE OF EVOLUTION BUT WE'VE
ALREADY LEARNED THAT STRUCTURAL
VARIANTS ARE REALLY IMPORTANT IN
COMPLEX NEUROPSYCHIATRIC
CONDITIONS, SPECIFICALLY IN LEWY
BODY DEMENTIA, MANY CASES, YOU
KNOW, IF YOU HAVE DUPLICATIONS
OF APP GENE OR SNCA GENE YOU'RE
AT HIGH RISK FOR DEVELOPING LEWY
BODY DEMENTIA, KNOWN RISK GENE
FOR LEWY BODY DEMENTIA.
AND SO WHAT WE THEN DID, WE USED
MODERN COMPUTATIONAL PIPELINE TO
MAP STRUCTURAL VARIANTS BASED ON
WHOLE GENOME SEQUENCE DATA, A
VERY INTENSE UNDERTAKING.
BUT IN DOING SO WE WERE ABLE TO
PERFORM THE VERY FIRST GENOME
WIDE STRUCTURAL VARIANT
ASSOCIATION STUDY IN LEWY BODY
DEMENTIA, AND LO AND BEHOLD
IDENTIFIED ANOTHER RISK GENE.
THERE WAS A 300 BASE PAIR DELAYS
IN TPCN1, ENDOLYSAL GENE, 1.4,
IT'S A RISK GENE.
WE VALIDATED, IT IS ACTUALLY
QUITE PREVALENT IN OUR PATIENT
POPULATION.
THE INTERESTING THING IS THAT
WHEN WE LOOK AT LITERATURE MORE
CAREFULLY, IT HAS BEEN SUGGESTED
AS A POSSIBLE RISK LOCUS FOR
ALZHEIMER'S DISEASE.
IT DIDN'T ACTUALLY REACH
SIGNIFICANCE AT THAT TIME, AND
SO WHAT WE DID THEN AS A NEXT
STEP IS WE DID FINE MAPPING AT
THE LOCUS, AT THE TPCN 1 LOCUS,
COMPARING LEWY BODY DEMENTIA TO
ALZHEIMER'S DISEASE, AND LEWY
BODY DEMENTIA TO PARKINSON'S
DISEASE.
WITH ALZHEIMER'S DISEASE VERSUS
LEWY BODY DEMENTIA WE SEE A
STRONG CORRELATION, ESSENTIALLY
SEE THE SAME RISK HAPLOTYPE
SHOWING UP SUGGESTING AN
IMPORTANT RISK LOCUS FOR
ALZHEIMER'S DISEASE,
SUBSEQUENTLY NOW ALSO BEEN
CONFIRMED.
BUT THIS IS IMPORTANT.
BUT INTERESTINGLY DOES NOT PLAY
A MAJOR ROLE IN PARKINSON'S
DISEASE.
SO THERE SEEMS TO BE PARTIAL
OVERLAP OF ALZHEIMER'S DISEASE
BUT NOT NECESSARILY WITH
PARKINSON'S DISEASE FOR EVERY
RISK LOCUS.
AND SO WHAT I'M GETTING TO THAT
IS INCREASINGLY WE'RE SEEING
THAT ONE GENE CAN PLAY AN
IMPORTANT ROLE IN MULTIPLE
DIFFERENT DISEASES.
I THINK ONCOLOGISTS ARE VERY
MUCH USED TO THIS TYPE OF
THINKING, FOR NEUROLOGISTS IT'S
NEW CONCEPTUALLY.
WE SEE NETWORKS THAT ARE
AFFECTED, THAT ARE SHIFTING.
AND THAT'S ACTUALLY REALLY GOOD
NEWS, BECAUSE IT IMPLICATES THAT
A LOT OF THESE REALLY
DEVASTATING DISEASE HAVE SHARED
BIOLOGY UNDER THE HOOD FROM A
CELLULAR LEVEL.
WE CAN LEVERAGE THAT TYPE OF
KNOWLEDGE TO PRIORITIZE WHICH
GENES WE SHOULD TARGET AND, YOU
KNOW, PERHAPS YOU CAN REPURPOSE
A DRUG THAT HAS BEEN DEVELOPED
LET'S SAY FOR ALZHEIMER'S
DISEASE NOW FOR LEWY BODY
DEMENTIA, VICE VERSA.
AND SO THERE'S ANOTHER EXAMPLE
WHERE WE SAW PLEIOTROPIC GENE
COME UP THAT WAS RATHER
SURPRISING.
WE LOOKED FOR KNOWN
DISEASE-CAUSING MUTATIONS AND
IDENTIFIED DAMAGING MUTATIONS IN
THE GENE CALLED PROGRANULIN.
IF YOU CARRY MUTATION IN THIS
PARTICULAR GENE, YOU KNOW THE
TEXT BOOK KNOWLEDGE IS YOU GET
FRONTOTEMPORAL DEMENTIA, A
DIFFERENT TYPE CHARACTERIZED BY
ABNORMAL DEPOSITION OF A PROTEIN
CALLED TDP-43.
BUT LO AND BEHOLD WE SAW
ENRICHMENT OF LOSS OF FUNCTION
DISEASES, IN OUR LEWY BODY
DEMENTIA PATIENTS.
AND THERE WAS OTHER HINTS THAT
PROGRANULIN COULD PLAY A ROLE
BASED ON GWAS SIGNALS IDENTIFIED
IN ALZHEIMER'S AND PARKINSON'S
DISEASE.
WHEN WE LOOKED AT THESE CASES
CAREFULLY WE DEFINITELY COULD
APPRECIATE YES THEY HAVE LEWY
BODY DEMENTIA, THEY HAVE LEWY
BODIES CLASSICAL FOR THE
DISEASE, BUT THEY ALSO HAVE
TDP-43 INCLUSIONS.
WE'RE LEARNING SOME OF THESE
CO-PATHOLOGIES THAT WE'RE OFTEN
SEEING IN THESE PATIENTS IS
ACTUALLY A MOLECULAR ETIOLOGY
UNDERNEATH IT.
AND ALTHOUGH THIS IS REALLY
RARE, IT IS INTERESTING FROM A
CLINICAL POINT OF VIEW BECAUSE A
LOT OF TARGETED INTERVENTIONS
FOR PROGRANULIN ARE ACTUALLY NOW
ALREADY IN THE CLINICAL TRIALS
PHASE.
AND SO SOME OF THESE PATIENTS
MAY REALLY BENEFIT FROM
INCLUSION.
AND THEY REALLY CAN LOOK LIKE
BONA FIDE AND LEWY BODY
DEMENTIA, IF YOU LOOK AT
CLINICAL ON THE LEFT-HAND SIDE.
THERE'S SO MANY LESSONS WE HAVE
LEARNED.
BUT ONE THING THAT WE REALLY
WANTED TO DELVE INTO FURTHER
BECAUSE WE HAVE THESE
PATHOLOGICALLY REALLY WELL
CHARACTERIZED CASES IS CAN WE
EXPLAIN SOME OF THE
CO-PATHOLOGIES AND OVERLAP WITH
ALZHEIMER'S DISEASE A LITTLE BIT
MORE CAREFULLY, SO WHAT WE DID
IS WE TOOK PATHOLOGICALLY
CONFIRMED CASES AND SUBDIVIDED
INTO THOSE THAT HAVE RELATIVELY
PURE LEWY BODY DEMENTIA AND
THOSE THAT HAVE LEWY BODY
DEMENTIA WITH ALZHEIMER'S
DISEASE CO-PATHOLOGY.
WHEN WE DO THAT WHAT WE SAW WAS
QUITE INTERESTING.
THE ONES THAT HAVE PURE LEWY
BODY DEMENTIA IN OVER 80% OF
CASES ARE MENTAL HEALTHS.
ARE MALES.
IT'S BEEN SEEN ACROSS
POPULATIONS, THERE'S A REAL
DIFFERENCE ACROSS THE SEXES.
ONCE WE HAVE ALZHEIMER'S
ALZHEIMER'S DISEASE
CO-PATHOLOGY WE CAN APPRECIATE
IN MANY CASES THOSE ARE THE
INDIVIDUALS THAT CARRY THE APOE
4 RISK ALLELE.
SO THAT SEEMS TO BE A REALLY
IMPORTANT DRIVER FOR THESE
MULTI-PROTEINIC CHANGES
HAPPENING.
WHAT'S GOING ON WITH THE PURE
CASES?
SO WHEN WE LOOK AT THE PURE
CASES, LOOK AT THE MOST COMMON
RISK ALLELES, WHAT WE'RE SEEING
IS THAT THOSE ARE VERY COMMONLY
THE ONES THAT HAVE THE GBA RISK
ALLELE.
AND SO WHAT THIS SUGGESTS IS
THAT SOME OF THESE HIGH RISK
ALLELES THAT WE'RE APPRECIATING
ARE REALLY TELLING US SOMETHING
ABOUT DISEASE SUBTYPES THAT
EXIST.
ONE OF THE MORE APOE 4 DRIVEN
BUT CO-PATHOLOGY AND ONE MALE
DRIVEN AND PURE IN PRESENTATION,
INTERESTING CLINICAL
CORRELATIONS AS WELL.
APOE 4 CARRIERS OFTEN HAVE
SHORTER SURVIVAL, PURE DLB CASES
HAVE PROMINENT CASES, THAT TELLS
US SOMETHING ABOUT THE DISEASE
AND ABOUT HOW WE SHOULD
POTENTIALLY DEVELOP CLINICAL
TRIALS.
WE MAY HAVE TO SUBSTRATIFY
PATIENT POPULATION TO RECOGNIZE
THESE SUBTYPES.
BUT BECAUSE WE'RE SEEING SO
INTERESTING SEX DIFFERENCES
ACROSS OUR PATIENT POPULATION WE
WERE ALSO WONDERING IF WE CAN
PERHAPS IDENTIFY GENETIC FACTORS
THAT COULD PLAY A ROLE THAT MAY
PLAY A ROLE, YOU KNOW, IN
EXPLAINING WHY WOMEN VERSUS MEN
HAVE DIFFERENT RISKS.
SO THIS IS, YOU KNOW, REALLY
JUST THE TIP OF THE ICEBERG, IN
MY HUMBLE OPINION.
WE DID A SO-CALLED CHROMOSOME X
WIDE ASSOCIATION STUDY WHERE WE
SUBDIVIDED COHORT IN MALES ONLY
VERSUS MALE CONTROLS, FEMALE
ONLY CASES VERSUS FEMALE ONLY
CONTROLS.
AND THEN CONDITIONED IT BASED ON
THE HIGH RISK APOE 4 ALLELE.
BUT WE WERE ABLE TO IDENTIFY
ANOTHER RISK SIGNAL IN, ONLY
SEEN IN FEMALES WITH THIS
DISEASE.
SO THIS IS AN INTERESTING
PATHWAY THAT WE'RE SEEING WHICH
IS THE MAP K PATHWAY, MULTIPLE
FUNCTIONS, PLAYs AN IMPORTANT
ROLE IN NEUROINFLAMMATORY
PROCESSES, IN RESPONSE TO
PROTEIN DEPOSITS, AND BASED ON
OUR FINDINGS MAY PLAY A
PARTICULAR IMPORTANT ROLE IN
WOMEN WITH THE DISEASE.
PERHAPS WHY WOMEN HAVE MORE
CO-PATHOLOGIES AND DON'T READ
THE TEXT BOOKS AS WE SAY BECAUSE
THEY PRESENT WITH MORE COMPLEX
FEATURES.
SO GENOMICS IS FUN BUT THERE ARE
OTHER LINES OF EVIDENCE THAT CAN
REALLY HELP US UNDERSTAND THE
DISEASE.
WHERE WE'VE BEEN WORKING
CAREFULLY OVER THE LAST COUPLE
YEARS TRYING TO MARRY THE TWO OF
THEM TOGETHER.
AND SO HERE IS AN EXAMPLE OF HOW
WE HAVE STUDIED -- USED
EPIDEMIOLOGICAL DATA TOGETHER
WITH OUR MOLECULAR DATA TO GAIN
IMPORTANT INSIGHTS INTO WHICH
DRUGS COULD BE POTENTIALLY
REPURPOSE AND USED FOR TREATMENT
OF LEWY BODY DEMENTIA.
SO THIS IS A STUDY THAT I'VE
DONE IN COLLABORATION WITH DR.
RUTH PFEIFFER, USED MEDICARE
DATABASE TO EXTRACT PATIENTS
WITH LEWY BODY DEMENTIA AND
MATCHED CONTROLS.
THOSE NUMBERS ARE SPECTACULAR.
I THINK AS FAR AS I KNOW THAT'S
THE LARGEST STUDY OF LEWY BODY
DEMENTIA ANYBODY HAS EVER DONE.
AND THE EXCITING THING IS WE HAD
A LOT OF, YOU KNOW, ANCESTRY
DIVERSE CASES AS WELL, SO ABOUT
20% OF OUR COHORT WERE FROM
DIVERSE ANCESTRY INDIVIDUALS.
AND WHAT WE ESSENTIALLY DID WAS
WE LOOKED AT INDIVIDUALS WHO
WERE DIAGNOSED WITH LEWY BODY
DEMENTIA, BUT THEN LOOKED THREE
YEARS PRIOR TO THAT, WHAT WERE
THE DRUGS THEY WERE TAKING FOR
ANY KIND OF ETIOLOGY, AND WERE
ANY OF THOSE DRUGS ASSOCIATED
WITH DECREASED RISK FOR
DEVELOPING THE DISEASE,
ESSENTIALLY WE DID A LARGE SCALE
VERY BROADLY ADJUSTED LOGISTIC
REGRESSION ANALYSIS.
ONE THING THAT STOOD OUT
CARDIOVASCULAR DISEASE RISK
MANAGEMENT DRUGS WERE
CONSISTENTLY ASSOCIATED WITH
DECREASED RISK FOR LEWY BODY
DEMENTIA.
I THINK IT CAPTURES SOMETHING
ABOUT THERE'S A BROADER
METABOLIC DYSFUNCTION ONGOING
BEFORE PEOPLE DEVELOP OR GET TO
THE DIAGNOSIS, THAT MAY BE
TREATABLE.
SO THIS IS POTENTIALLY DISEASE
MODIFICATION AT OUR FINGERS
TIPS.
ANTI-DIABETICS,
ANTI-HYPERTENSIVE, CHOLESTEROL
LOWERING MEDICATION, A FEW
OUTLIERS, REVERSE CAUSE
INDICATION, PEOPLE WITH
PRODROMAL FEATURES SUCH AS
TREMOR.
EPIDEMIOLOGICAL DATA ARE MESSY,
REAL WORLD ELECTRONIC HEALTH
RECORDS DATA, WE WANTED TO SEE
IF WE CAN LEVERAGE GENOMIC
INFORMATION TO CONFIRM THAT
THESE OBSERVATIONS ARE REAL,
THERE'S NOT CONFOUNDING THAT'S
DRIVING THIS.
WE WENT TO OUR VERY CAREFUL AND
DEEPLY PHENOTYPED GENOME
SEQUENCING DATASETS.
WE LEVERAGED A METHODOLOGY THAT
ALLOWS US TO DRAW CAUSAL
RELATIONSHIPS.
SO IN ESSENCE YOU TAKE THE
GENOME WIDE ASSOCIATION STUDIES,
SUMMARY STATISTICS FROM
CARDIOVASCULAR DISEASE TRAITS
SUCH AS HYPERTENSION, DIABETES,
LDL CHOLESTEROL LEVELS, AND SEE
HOW THEY ARE CORRELATED.
AND SO WHEN WE LOOK AT THAT WE
COULD CLEARLY APPRECIATE THAT
THERE WAS A GENETIC OVERLAP IN
THE GENETIC ARCHITECTURE OF
THESE CARDIOVASCULAR DISEASE
TRAITS AND LEWY BODY DEMENTIA.
AND BASED ON THE MIXER MODELING
COULD DEMONSTRATE THIS IS A
CAUSAL RELATIONSHIP, SO WE SEE
LEFT DEFLECTION ON THE LEFT-HAND
KIND OF PLOT, WHICH IS THE
SIGNATURE FOR CAUSAL
RELATIONSHIPS.
AND SO WHAT THIS MEANS IS THAT
CARDIOVASCULAR DISEASE TRAITS
ARE REALLY PART OF THE DISEASE
PHENOTYPE, REALLY IS EXCITING
BECAUSE THESE ARE ALL MODIFIABLE
RISK FACTORS.
SO THIS IS -- POTENTIAL DISEASE
MODIFICATION AT OUR FINGERTIPS
RIGHT NOW, IN LINE WITH EVIDENCE
WE'VE SEEN IN ALZHEIMER'S AND
PARKINSON'S DISEASE, RISK
FACTORS ARE A MAJOR DRIVER FOR
NEURODEGENERATION, SO THIS IS
SOMETHING WE NEED TO THINK ABOUT
MORE CAREFULLY IN THE CLINIC AS
WE TREAT PATIENTS AND TRY TO
DESIGN CLINICAL TRIALS.
WE TAKE A SNAPSHOT WITH RESPECT
TO LEWY BODY DEMENTIA, SO
DEFINITELY THE DISEASE THAT
OVERLAPS IN ITS ARCHITECTURE
WITH OTHER NEURODEGENERATIVE
CONDITIONS SUCH AS ALZHEIMER'S
DISEASE, FRONTOTEMPORAL,
VASCULAR DEMENTIA, PARKINSON'S
DISEASE, AND MANY RISK GENES
THAT I PUT NICELY THERE ON THE
SO-CALLED PLOT HAS BEEN
DESCRIBED IN THESE DISEASES.
I THINK A NICER WAY TO
DEMONSTRATE WHAT THEY ARE IS BY
LOOKING AT THE CELLULAR
FUNCTIONS, PATHWAYS THEY MAP TO.
ONE IMPORTANT PATHWAY, ONE
IMPORTANT FUNCTION, IS
ENDOLYSOSOMAL FUNCTIONS, WE
OFTEN SEE DYSFUNCTION IN THE
PATHWAY, IN THE LEWY BODY
DEMENTIA PATIENT POPULATION.
ANOTHER IMPORTANT PATHWAY IS
AMYLOID PATHWAY, SO THAT'S
AMYLOID PRECURSOR PROTEIN OFTEN
DEPOSITED IN ALZHEIMER'S DISEASE
AND LEWY BODY, SHOWING UP IN
LEWY BODY DEMENTIA PATIENT
POPULATION.
GENES THAT ARE PLAYING AN
IMPORTANT ROLE IN
NEUROTRANSMISSION AND
NEUROINFLAMMATION, SO THIS THING
IS SOMETHING THAT WE'RE SEEING
AGAIN AND AGAIN, USUALLY THE SUM
OF THE PARTS IS GENE IN CONCERT
WITH AGING THAT WE THINK IS
TIPPING THE CELL INTO DISEASE
ULTIMATELY RESULTING IN
NEURODEGENERATION.
WHAT ARE WE GOING TO DO WITH
THAT?
IT'S A NICE ACADEMIC EXERCISE,
TO FIGURE THESE THINGS OUT, BUT
AT THE END OF THE DAY THESE ARE
DEVASTATING DISEASES.
SO WE WANT TO GET TO A POINT
WHERE WE WANT TO DO SOMETHING
ABOUT IT.
AND SO ALREADY WE'RE USING
GENETICS IN FAMILIAL CASES TO,
YOU KNOW, IMIMPROVE COUNSELING
OF PATIENTS AND FAMILIES.
IT ALLOWS US TO ENROLL PATIENTS
IN CLINICAL TRIALS, REALLY
TARGETS CERTAIN GENETIC FORMS OF
THE DISEASE, BUT REALLY HELPS US
ALSO WITH DISEASE MODELING, A
LOT OF OUR PATIENTS PROVIDING,
FOR EXAMPLE, BLOOD SAMPLES THAT
CAN BE CONVERTED INTO STEM CELLS
AND WE CAN DO A LOT OF IN VITRO
MODELS NOW PROVING A LOT OF
THESE INTERESTING OBSERVATIONS
IN A DISH, ACCELERATING
THERAPEUTIC DEVELOPMENT.
BUT EVEN FOR THE NON-FAMILIAL
CASES THERE'S IMPORTANT INSIGHT
WE ALREADY GAINED THAT REALLY
ARE INSPIRING US, TRANSLATIONAL
IMPLICATIONS IN OUR GRASP.
WE'VE IDENTIFIED IMPORTANT
GENES, IMPORTANT PATHWAYS, MANY
ARE SHARED, WITH OTHER DISEASES,
THAT REALLY TELLS US SOMETHING
ABOUT OPPORTUNITIES TO TREAT A
BROADER SPECTRUM OF CONDITIONS.
WE ARE SMARTER NOW IN TERMS OF
RECOGNIZING DISEASE SUBTYPES
THAT WE CAN DEFINE GENETICALLY
SIMPLE PCR GENOTYPING, NOTHING
SPECIAL ABOUT IT, THAT CAN
PERHAPS HELP US IDENTIFY
INTERESTING SIGNALS AS MAY HAVE
BEEN MISSED IN CLINICAL TRIALS.
WE CAN USE MOLECULAR DATA TO
REPURPOSE AND HIGHLIGHT DRUGS
THAT CAN BE USED.
I THINK OVERALL THIS IS A VERY
IMPORTANT DEVELOPMENT BECAUSE
GENOMICS INCREASINGLY IS REALLY
ACCELERATING THE DRUG
DEVELOPMENT PIPELINE.
THERE'S A LOT OF ADVANCES
ALREADY IN OTHER FIELDS THAT ARE
A LITTLE BIT FURTHER ALONG, HAVE
BIGGER NUMBERS, BUT WE'RE
STARTING TO CATCH UP.
SO, FOR EXAMPLE, STATINS,
MILLIONS OF PEOPLE TAKE STATINS
FOR HIGH CHOLESTEROL LEVELS,
REALLY HAS BEEN BASED ON A
GENETIC DISCOVERY, NOW THIS IS
REALLY A GAME CHANGER.
AND SO WE'RE VERY HOPEFUL THAT A
LOT OF THESE DISCOVERIES,
INSIGHTS, WILL ULTIMATELY RESULT
IN NEW THERAPIES.
AND, YOU KNOW, THERE'S GOOD
REASON TO BE OPTIMISTIC, A THIRD
OF FDA-APPROVED DRUGS ALREADY
HAVE GENETIC SUPPORT AND THAT
NUMBER IS REALLY INCREASING AS
WE'RE GETTING BETTER WITH OUR
GENETIC MODELING, AND THE MORE
GENETIC EVIDENCE WE HAVE, THE
HIGHER THE SUCCESS RATE IS.
AND SO, YES, WHILE A LOT OF
THINGS ARE PUSHING INTO THE
CLINIC, WE STILL HAVE TO DO A
LOT OF WORK.
THERE ARE THINGS WE HAVEN'T
REALLY STUDIED EXTENSIVELY.
THINGS LIKE SOMATIC MUTATIONS,
SO IN ORDER TO CAPTURE THAT WE
HAVE TO DO DEEP SEQUENCING TO
PICK THEM OUT.
THERE ARE VARIANTS WHERE WE ARE
UNDERPOWERED.
OURS IS THE LARGE FOR LEWY BODY,
SMALL FOR GENOMICS, WE NEED TO
EXPAND INTERACTIONS FROM ONE
GENE TO ANOTHER THAT WE COULDN'T
MODEL STATISTICALLY.
THERE ARE OTHER TYPES OF GENETIC
VARIANTS THAT WE CAN'T REALLY
MAP VERY WELL.
SO, FOR EXAMPLE, TELL TELOMERE
REGION, COULD PLAY AN IMPORTANT
ROLE, WE MAY BE MISSING A LOT.
I'M A GENETICIST.
I ADMIT THE ENVIRONMENT IS STILL
VERY IMPORTANT AND THOSE
INTERACTIONS IS SOMETHING WE
HAVE TO THINK ABOUT MORE
CAREFULLY.
THERE MAY BE OTHER THINGS WE
HAVEN'T YET THOUGHT B I DON'T
--
THOUGHT ABOUT.
I DON'T CLAIM ALL THE ANSWERS
WE'RE.
WE'VE MORE THAN DOUBLED COHORT
SIZE, CURRENTLY ALIGNING THE
GENOMES.
WE HAVE REALLY DOUBLED DOWN IN
TRYING TO INCREASE DIVERSITY.
A LOT OF BRAIN BANKS HAVE A
BIASED COLLECTION, WE DON'T HAVE
A LOT OF DIVERSITY IN THEM.
I'VE BEEN PARTNERING WITH A LOT
OF PROGRAM DIRECTORS FOR PDPP
AND ALL BRAIN BANKS TO GET LEWY
BODY CASES FROM ANCESTRY DIVERSE
INDIVIDUALS.
AND WE'RE TRYING TO REALLY
EXPAND OUR FOUNDATIONAL GENOMIC
RESOURCES, ALSO LEVERAGE
RESOURCES THAT OTHERS ARE
GENERATING LIKE TRANSCRIPTOMIC
CATALOGS THAT DON'T HAVE TO BE
FROM MY PATIENT OF INTEREST.
I CAN USE COMMON VARIANTS AND
CAN PREDICT WHAT THEY ARE DOING
BASED ON CATALOGS OF COMMON
VARIANTS.
AND INCREASINGLY USING
COMPUTATIONAL TOOLS WE CAN USE
MULTI-OMIC DATA INTEGRATION TO
REALLY INTERPRET OUR FINDINGS IN
SYSTEMS BIOLOGY FRAMEWORK.
AND WE HAVE DONE SIMILAR THINGS
NOW WITH OTHER DISEASES, FOR
EXAMPLE MULTIPLE SYSTEM ATROPHY,
AND WE'RE NOT THE ONLY ONES
WORKING AND ACCELERATING THE
FIELD, ABLE TO PINPOINT
MOLECULAR UNDERPINNINGS IN
AGE-RELATED DISEASES EVEN IN
THOSE THAT ARE SPORADIC, SO
SUSCEPTIBILITY GENES, GENE
MODIFIERS STILL PLAYING A ROLE,
THAT KNOWLEDGE IS WORTHWHILE.
IT'S WORTH THE EFFORT OF TRYING
TO PUT IT TOGETHER.
WE NOW HAVE CAPABILITIES TO
STUDY THESE DISEASES IN THE
BROADER COMPLEX, SIDE BY SIDE,
COMPARISONS, LOOKING AT OVERLAP
IN ARCHITECTURES.
AND, YOU KNOW, THIS IS ALREADY
REALLY GEARING UP TOWARDS
GETTING TOWARDS TRANSLATIONAL
APPLICATIONS.
SO WHERE WE ARE RIGHT NOW IS
WE'RE STILL GATHERING MOLECULAR
KNOWLEDGE BUT WE'RE ALREADY
USING GENETICS INCREASINGLY TO
HELP US WITH THE DIAGNOSTIC
IMPRESSION.
WE'RE USING IT AS A BIOMARKER TO
SUBSTRATIFY INDIVIDUALS, AND,
YOU KNOW, WE ALREADY, YOU KNOW,
ARE COMING UP WITH BETTER WAYS
TO POTENTIALLY DO GENE THERAPY
TRIALS AND WHAT GENES AND
TARGETS WE SHOULD USE AND
HOPEFULLY BY PUTTING THESE
EFFORTS TOGETHER KEEPING WORKING
ON THAT PATH, WE CAN GET TO THE
POINT WHERE WE CAN GET THE RIGHT
THERAPY TO THE RIGHT PATIENT AT
THE RIGHT POINT OF TIME AND MAKE
A REAL DIFFERENCE IN THE LIVES
OF PATIENTS WHO ARE DEVASTATED
BY THESE SERIOUS
NEURODEGENERATIVE DISEASES.
KEY MESSAGE, THERE'S BEEN
MASSIVE ADVANCES IN GENOMICS.
AND WE'RE FINALLY REALLY
STARTING TO GET A HANDLE AT
THESE COMPLEX NEURODEGENERATIVE
DISEASE THAT HAVE UNTIL NOW HAVE
BEEN VERY DIFFICULT TO TACKLE.
AND SO USING EXAMPLE OF LEWY
BODY DEMENTIA IT'S A COMPLEX
DISEASE, INTERSECTS WITH OTHER
AGE-RELATED NEURODEGENERATIVE
DISEASES, MANY PLEIOTROPIC GENES
AND THESE ARE REALLY INTERESTING
FROM A THERAPEUTIC TARGETING
POINT OF VIEW.
AND INCREASINGLY WE'RE EXPANDING
OUR EFFORTS TO REALLY GET
TOWARDS TRANSLATIONAL GENOMICS
AND BRING THOSE THERAPIES TO THE
PATIENTS.
AND SO ALL OF WHAT I DO HERE IS
TEAM SCIENCE.
THERE'S NOTHING THAT REALLY AM
DOING HERE.
SO I OWE A LOT OF GRATITUDE TO
THE MANY PEOPLE WHO HAVE BEEN
CONTRIBUTING.
I CANNOT FIT EVERYBODY ON THE
SLIDE HERE.
BUT I ALSO WANT TO SAY SPECIAL
THANKS TO THE PATIENTS AND
FAMILIES WHO WORK WITH US, WHILE
THEY ARE FACING VERY DIFFICULT
SITUATIONS.
WE'LL KEEP GOING.
SO THANK YOU VERY MUCH FOR YOUR
TIME.
AND I'M HAPPY TO TAKE A COUPLE
OF QUESTIONS RIGHT NOW.
[APPLAUSE]
>> IF YOU HAVE A QUESTION PLEASE
GO TO THE MICROPHONE SO THE
OUTSIDE WORLD CAN HEAR.
THANK YOU.
>> BY THE TIME A PATIENT
DEVELOPS COGNITIVE DYSFUNCTION,
THE NEURODEGENERATION IS ALSO
ADVANCED.
HOMEOSTATIC MECHANISMS THAT THE
BODY HAS HAVE BEEN OVERWHELMED.
WHAT CAN YOU DO TO IDENTIFY THE
GENETIC RISK BEING ACTUALLY
TRANSLATED INTO NEUROPATHOLOGY
IN PRE-CLINICAL PHASE?
>> YEAH, SO THERE'S A LOT OF
DISCUSSIONS OBVIOUSLY.
WE NEED TO IDEALLY IDENTIFY
DISEASE AS EARLY AS POSSIBLE.
AND SO INCREASINGLY, WE'RE
UTILIZING BIOMARKERS THAT CAN
DETECT ABNORMALLY DEPOSITED
PROTEIN.
EITHER IN THE CSF USING
DEAGGREGATION ASSAYS SUCH AS RT
QUICK, WE CAN ALSO USE SKIN
BIOPSIES, STILL TRYING TO
UNDERSTAND HOW LONG PATHOLOGICAL
PROTEIN DEPOSITS EXIST IN THE
PRESYMPTOMATIC SPACE.
WITH SKIN BIOPSIES WE'RE SEEING
INDIVIDUALS VERY YOUNG,
NEUROLOGICALLY HEALTHY, IT'S
VERY DIFFICULT TO SAY WHAT IS
YOUR PROGNOSIS, BUT THOSE ARE
THE INDIVIDUALS WE WOULD LIKE TO
FOLLOW VERY CAREFULLY.
IT'S THE COMBINATION OF VERY
CLINICAL ASSESSMENT WITH NEW
BIOMARKERS, NEW IMAGING MARKERS,
POTENTIALLY ALSO NEW PET LIGANDS
SPECIFIC TO SYNUCLEIN IN THE
PIPELINE WE WILL BE ABLE TO
IDENTIFY THESE INDIVIDUALS AND
TRY TO GET THEM INTO CLINICAL
TRIALS, DISEASE MODIFYING, PUT
THEM ON DISEASE-MODIFYING
AGENTS.
MAY NOT BE A CURE BUT EVEN A
SLOWING DOWN OF THE DISEASE
WOULD BE WORTH THE EFFORT.
>> SO, THIS WORK IS AMAZING.
I LOVE IT, RIGHT?
SO WE'VE GOT -- WE'RE BREAKING
THIS IDEA OF GENE TO DISEASE.
AND EXTREMELY WILL SAY GENES ARE
REAL BUT DISEASES MIGHT NOT BE,
BEING DELIBERATELY PROVOCATIVE
THERE.
RIGHT.
LET'S TAKE THE EXAMPLE OF APOE,
HOW WE COULD TACKLE THIS.
MAYBE APOE IS A PROCESS OF
DEMENTIA IRRESPECTIVE OF
TAUOPATHY, HOW COULD WE TACKLE
THAT?
I'D LOVE TO HEAR YOUR THOUGHTS
ON THAT.
>> YEAH, IN PARTICULAR APOE I
THINK IS A VERY EXCITING
POTENTIAL TARGET FOR THERAPY
DEVELOPMENT, IT'S BEEN
IMPLICATED IN VASCULAR, LEWY
BODY, ALZHEIMER'S, A BIG ONE,
REFLECTIVE OF THE FACT THERE'S A
BROAD METABOLIC DYSFUNCTION WITH
AGING.
BASED ON THE ANIMAL MODELS, FOR
EXAMPLE, WORKING WITH RON
CRYSTAL'S LAB, YOU CAN ACTUALLY
TARGET THE APOE 4 ALLELE AND
INSERT, FOR EXAMPLE, USING GENE
THERAPIES AND APOE 2 ALLELE AND
SLOW DOWN THE DISEASE PROCESS.
SO THAT'S ONE OF THE ANIMAL
MODELS THAT'S REALLY VERY
EXCITING.
THERE'S ALSO POTENTIAL FOR
ENGINEERING, SO AS YOU KNOW
THERE'S CHRIST CHURCH VARIANT
THAT IMPARTS RESILIENCE TO
AMYLOID PATHOLOGY, THEY HAVE
PATHOLOGY BUT DON'T DEVELOP
DEMENTIA, FOR SOME REASON DON'T
GET THE NEURODEGENERATION.
SO PERHAPS BIOENGINEERING THESE
CHRISTCHURCH VARIANT WE MAY BE
ABLE TO STOP THE DISEASE PROCESS
IN THOSE HIGH RISK INDIVIDUALS
WITH LET'S SAY APOE 4 ALLELE,
IT'S SO PREVALENT, SO COMMON, SO
MANY FUNCTIONS, I COULD SEE IT
WHEN PEOPLE ENTER MIDDLE AGE,
UNFORTUNATELY AFFECTS ME, WOULD
GET SCREENED FOR, THAT MAY
INDIVIDUALIZE FOLLOW-UP
TREATMENT FOR HYPERLIPIDEMIA,
VASCULAR RISK FACTORS PART OF
THE DISEASE PROCESS.
I COULD SEE THERE ARE TARGETED
GENE THERAPIES FOR APOE COMING
AND BASED ON METABOLIC
DYSFUNCTIONS.
THANK YOU, GREAT QUESTION.
>> FANTASTIC.
I JUST LOVED IT.
ESPECIALLY YOUR THIRD HALF ON
THE DRUG STUFF.
A SIMPLE QUESTION.
SOME DRUGS, THREE CONDITIONS
THAT ARE ASSOCIATED WITH THE
VASCULAR, HYPERTENSION,
DIABETES, HIGH LDL, SO THERE IS
ALREADY A CLASSIC COMPOUND, I
DON'T KNOW IF IT HAS SHOWN ON
THE SCREEN.
PREF A STATIN LOWERS LDL AND
ANTI-INFLAMMATORY DISEASES,
WHICH COMPONENT IS CAUSING
DISEASE, DID YOU SEE DIFFERENCE
IN YOUR WHOLE -- YOU HAD 2500
PEOPLE, WERE SOME ALREADY ON A
STATIN FOR EXAMPLE AND DID THEY
HAVE LESS THAN THE ONES THAT
DIDN'T?
YOU KNOW WHAT I MEAN?
>> SO IN OUR LDD COHORT WE
DIDN'T HAVE THE DRUG
INFORMATION.
THE ONES WE GENOME SEQUENCED, SO
WE MADE INTERESTING OBSERVATIONS
IN THE DATA SOCIETY AND --
DATASET, ONE OF THE STRONGEST
ASSOCIATED DUGS THAT CAME UP WAS
AN ANTI-HYPERTENSIVE NOT
COMMONLY PRESCRIBED, CARVELALOL,
A BETA BLOCKER.
WHAT'S GOING ON THERE?
IT IS A VERY POTENT ANTIOXIDANT
AS WELL.
MORE POTENT THAN VITAMIN E.
I WONDER WHETHER WE'RE TARGETING
BY HAPPENSTANCE TWO PROCESSES.
THERE ARE MORE DRUG REPURPOSING
PIPELINES WE CAN APPLY WITH
BIGGER COHORT.
WE'RE STILL ON THE LOWER END
WHERE WE CAN SPECIFICALLY LOOK
AT THESE RELATIONSHIPS AND THESE
PATHWAYS, AND THESE DIRTY DRUGS
THAT HIT MULTIPLE PATHWAYS ARE
THE ONES MOST INTERESTING FOR
REPURPOSING.
>> A SECOND THOUGHT CAN YOU TELL
WELL IN ADVANCE WHEN SOMETHING
IS GOING TO BE A PROBLEM, LIKE
FOR ELEVATED SUGARS, BY THE TIME
YOU COME TO 110 YOU KNOW YOU'RE
GOING TO DO DIABETES AND YOU
NEED TO DO SOMETHING FAST.
YOU NEED SOMETHING SIMPLE, WELL,
NOT SIMPLE, BUT YOU KNOW WHAT I
MEAN.
IF THERE WAS ONE OR TWO
BIOMARKERS, I LIKE THE WAY
YOU'RE TALKING ABOUT BIOMARKERS,
ONE OR TWO THINGS THAT WILL TELL
YOU A MARKER, THAT WILL TELL
YOU, YES, YOU HAVE THAT PROBLEM,
THIS IS GOING TO OCCUR IF YOU
DON'T GO ON THIS, WHATEVER, ARE
WE CLOSE TO THAT YET?
>> SOMETHING WE WOULD LIKE TO
DO.
I MEAN, I'M OPTIMISTIC WE'RE
GETTING TO THAT POINT.
ESPECIALLY THE PROTEOMICS FIELD
RAPIDLY ADVANCING, REALLY
EXCITING.
YOU CAN PICK UP
NEURODEGENERATION QUITE EARLY
ON, LET'S SAY THROUGH MEASURING
NEUROFILAMENT, WE CAN START TO
PICK IT UP BUT I DON'T YET HAVE
THE ANSWER AS TO HOW SPECIFIC IT
IS AND HOW GOOD IT IS FOR
DISEASE PREDICTION.
MAY BE MULTI-MODAL BIOMARKERS
THAT WE'LL HAVE TO DEVELOP.
OTHER DISEASES ARE FURTHER
ALONG, PARKINSON'S DISEASE, YOU
KNOW, DIFFERENT PANELS OF
PROTEINS THAT CAN PREDICT THE
DISEASE BUT I THINK LEWY BODY
DEMENTIA WE'RE JUST GETTING
THERE.
BUT WE HAVE THE TECHNOLOGIES NOW
AND WE'RE PULLING EVERYTHING
TOGETHER.
THIS IS A REALLY IMPORTANT POINT
TO LOOK AT PREDICTION.
>> THANK YOU.
>> MICHAEL, WOULD IT BE OKAY IF
I SLIP IN AND ONLINE QUESTION?
WE HAVE SEVERAL ONLINE
QUESTIONS.
THE FIRST ONE WAS DO THESE
DUPLICATION OR TRANSLOCATION OF
LEWY BODY DEMENTIA GENES OCCUR
AT BIRTH OR DO THEY OCCUR DURING
THE HUMAN LIFE CYCLE?
AND HOW CAN THESE MUTATIONS
CAUSE ONLY PHENOTYPE ONLY IN OLD
PEOPLE, WHY DOES IT NOT OCCUR
EARLIER.
>> GREAT QUESTION.
I CAN ANSWER EVERY ASPECT BUT
THESE ARE GERMLINE MUTATIONS
THAT PEOPLE CARRY AS THEY ARE
BORN ALREADY.
AND WHY IS THERE, YOU KNOW,
DECREASED PENETRANCE AND WHY DO
SOME OF THESE RISK GENES NOT
CAUSE DISEASE EARLIER, THAT'S A
QUESTION WE ASK A LOT.
WE DON'T ALWAYS HAVE THE RIGHT
KIND OF ANSWERS.
I THINK IT'S PROBABLY PART OF
THE NORMAL AGING PROCESS THAT A
LOT OF THESE PATHWAYS WE HAVE A
LOT OF RESILIENCE BUILT IN, BUT
AS WE'RE AGING A LOT OF THESE
PATHWAYS START TO BECOME
IMPAIRED AND IF YOU ALREADY HAVE
A HIGH RISK GENE PERHAPS IN
CONJUNCTION WITH OTHER RISK
FACTORS MAYBE DIABETES,
HYPERTENSION, THAT MAY BE ENOUGH
TO TIP YOU INTO DISEASE.
BUT THERE MAY BE OTHER
PROTECTIVE FACTORS THAT COULD
EXPLAIN WHY THERE'S DECREASED
PENETRANCE.
WE DON'T HAVE ALL THE ANSWERS AS
OF YET.
>> OKAY.
>> TERRIFIC TALK.
THANK YOU.
I HAD A QUESTION ABOUT ANIMAL
MODELS.
YOU MENTIONED TOWARDS THE END
THAT THE GENOMICS REALLY INFORMS
DEVELOPMENT OF NEW MODELS.
AND ONE OF THE ISSUES IT SEEMS
TO ME IN THIS DISEASE WHICH IS A
CONTINUUM OF NEURODEGENERATIVE
DISEASES IS THE EFFECT OF ADDING
A BUNCH OF MUTATIONS, MAYBE
ENVIRONMENTAL FACTORS,
STOCHASTIC IN WHAT DISEASE YOU
GET?
IN OTHER WORDS TO SOME EXTENT
RANDOM, DEPENDING ON WHAT
HAPPENS FIRST, OR IS IT
DETERMINISTIC, IF YOU ADD GENE
XYZ YOU ALWAYS GET LEWY BODY
DEMENTIA, AND SO ON?
ARE THERE ANY GOOD ANIMAL MODELS
TO TEST THAT QUESTION?
>> SO A LOT OF ANIMAL MODELS
ARE ESSENTIALLY BASED ON THE
FAMILIAL FORMS OF THE DISEASE.
AND MANY OF THEM ARE ALSO
INCLUDING MUTATIONS THAT
OVEREXPRESS LET'S SAY
ALPHA-SYNUCLEIN OR INCREASE
LIKELIHOOD OF PROTEIN
DEPOSITION.
SO IN A WAY, THESE ARE REALLY
TOXICS CELLULAR ENVIRONMENTS, I
DON'T KNOW TO WHICH EXTENT THEY
REFLECT WHAT'S GOING ON IN A
SPORADIC CASE WITH A MORE
AGE-RELATED DISEASE SO IT'S VERY
DIFFICULT TO COMMENT ON
ENVIRONMENTAL FACTORS THAT MAY
PLAY A MILDER ROLE.
BUT AT LEAST IN GENETIC MODELS
YOU DO SEE, YOU KNOW, PROTEIN
DEPOSITION, YOU DO SEE
NEUROINFLAMMATION VERY EARLY ON.
WE SEE, YOU KNOW, THE NEURONAL
CELL POPULATIONS VERY MUCH
AFFECTED BUT INCREASINGLY ABLE
TO APPRECIATE GLIAL CELLS ARE
STARTING TO MALFUNCTION SO
MICROGLIAL DYSFUNCTION IS
SOMETHING WE CLEARLY APPRECIATE.
UNFORTUNATELY WE DON'T REALLY
HAVE GOOD DATA ON OLIGO
DENDRITIC BUT WORK ON
MULTI-SYSTEM ATROPHY
REAPPRECIATE SYNUCLEIN BIOLOGY
AND OLIGO NUCLEAR BIOLOGY ARE
RELATED.
WE'RE STILL TRYING TO IDENTIFY
WHAT IS THE BEST MODEL FOR OUR
DISEASE OF INTEREST, AND SOME IS
ARTIFICIAL BUT AT LEAST WE'RE
STARTING TO DISENTANGLE SOME OF
THE CRUCIAL STEPS OF PROTEIN
DEPOSITION, REALLY AN EARLY
EVENT THAT IS HAPPENING IN THESE
INDIVIDUALS.
>> YOU'RE LIMITED TO THE MOUSE
AT THIS POINT?
OR YOU'RE THINKING ABOUT OTHER
MODELS, NON-HUMAN PRIMATE?
>> YEAH, THERE ARE GROUPS THAT
ARE WORKING ON MACAQUES NOW.
SO THAT IS ONE ANIMAL MODEL THAT
ESPECIALLY FOR DRUG DEVELOPMENT
PIPELINE MAY BE MORE RELEVANT
BUT MOST IS REALLY FOCUSED ON
MOUSE MODELS.
THERE HAS BEEN A FAMILIAL
OCCURRENCE OF LEWY BODY DEMENTIA
IN PARROTS.
PARROTS APPARENTLY CAN ALSO GET
DEMENTIA.
IF SOMEBODY WANTS TO UNDERTAKE A
STUDY ON PARROTS --
>> CAN I SLIP IN ANOTHER?
THANK YOU.
HERE'S ANOTHER QUESTION FROM
ONLINE.
HAVE YOU LOOKED AT ALCOHOL AND
SUBSTANCE USE DISORDERS IN THE
LEWY BODY DEMENTIA PATIENT
COHORT THAT YOU ANALYZED, AND
HOW THESE DISORDERS COMPARE WITH
CBD THAT YOU MENTIONED
CORRELATED WITH LEWY BODY
DEMENTIA?
>> GREAT QUESTION.
SHORT ANSWER WE HAVEN'T LOOKED
AT OTHER COMORBIDITIES THAT
COULD PLAY A ROLE SO ALCOHOL IS
CERTAINLY A MAIN TOXIN.
AND SO I CAN'T REALLY COMMENT AS
TO WHICH EXTENT IT MAY PLAY A
ROLE.
CERTAINLY NOT HEALTHY AS
NEUROLOGISTS, I SAY THE LESS
ALCOHOL, THE BETTER.
BUT IT'S PROBABLY NOT THE ONLY
ANSWER.
SO HEALTH AND LIFESTYLE FACTORS
IS STILL SOMETHING EVERYBODY
SHOULD STICK TO AS MUCH AS
POSSIBLE.
>> THANK YOU FOR YOUR TALK.
IT WAS REALLY INTERESTING.
I WANTED TO ASK YOU FIRST ABOUT
THE -- WHEN YOU SHOWED --
ANALYZING THE GENOMIC NETWORKS
FOR TRYING TO CHARACTERIZE SOME
PATIENTS AS HAVING PURE LEWY
BODY DEMENTIA VERSUS MORE
ALZHEIMER'S-LIKE OR
DEMENTIA-LIKE, IF YOU WERE TO
JUST TRY TO CHARACTERIZE THE
NETWORK BASED ON GENOMICS ITSELF
AND NOT THINKING ABOUT THE
ALZHEIMER'S OR DEMENTIA, HOW
MANY DIFFERENT SUBTYPES COULD
YOU KIND OF SEE?
THE SECOND PART OF MY QUESTION
WAS ALSO WHAT ROLE DO YOU THINK
THAT VIRAL INFECTIONS, IF ANY,
MIGHT PLAY IN THE PROGRESSION,
LIKE IN ACTUALLY -- EITHER IN
EITHER INFECTIOUS VIRUS OR
LATENT VIRUS, THAT MIGHT BECOME
ACTIVE AS THE IMMUNE SYSTEM
BREAKS DOWN AS PEOPLE AGE?
>> YEAH, GREAT QUESTIONS.
WE HAVEN'T BROKEN DOWN THE
NETWORK FURTHER.
WE'VE LOOKED FROM DIFFERENT
ANGLES.
BUT WHEN IT COMES TO VIRAL
INFECTION, THAT'S A REALLY HOTLY
DEBATED TOPIC.
I THINK COLLABORATING WITH STEVE
JACOBSON AT NINDS, TO GET AT
THAT, WE USED OUR COHORT OF DATA
TO LOOK AT VIRAL SEQUENCES THAT
MAY BE INTEGRATED IN LEWY BODY
DEMENTIA AND IN ALZHEIMER'S
DISEASE.
WE DIDN'T SEE ANYTHING
ASSOCIATED WITH ALZHEIMER'S
DISEASE WE DID SEE INCREASE IN
VIRAL SEQUENCES IN LEWY BODY
DEMENTIA, IN RARE INSTANCES,
ALSO IN MULTIPLE SYSTEM ATROPHY,
ANOTHER SYNUCLEINOPATHY.
IT'S JUST AN OBSERVATION,
WHETHER THIS IS SECONDSARY
BECAUSE CHROMATIN IS OPENING UP,
WILDLY TRANSCRIBED, VIRAL
SEQUENCES BECOME ACTIVE, OR IS
IT IN ANY WAY CAUSALLY RELATED.
THE CONCERN IS THOSE INDIVIDUALS
THAT HAVE VIRAL REACTIVATION
THAT MAY EXACERBATE INFLAMMATORY
PROCESS AND COULD BECOME A
RUNAWAY DISEASE MECHANISM,
THAT'S A VERY INTERESTING
QUESTION.
THANK YOU.
>> I'M GOING TO TRY ANOTHER ONE
THAT I THINK SOMEBODY IS JUST
MESSING WITH ME HERE.
THANK YOU FOR SHARING YOUR WORK.
SEVERAL OF THE RARE PEDIATRIC
LYSOSOMAL DISEASES, e.g.
NEURONAL LIPO FUSION OSIS, PICK
DISEASE TYPEC HAVE N
EURODEGENERATIVE FEATURES, DO
THESE COME UP OR OPPORTUNITIES
TO LOOK FOR GENES CODING FOR
LYSOSOMAL GENES.
>> THEY ARE SOMETHING WE NEED TO
LOOK -- HAVE BEEN LOOKING AT
CAREFULLY.
SO PROGRANULIN IS ONE EXAMPLE
FOR LYSOSOMAL GENE, WE SEE
ENRICHMENT.
WE'VE LOOKED AT A COUPLE OTHERS.
SO FOR EXAMPLE NEWMAN PICC
DISEASE, WE CAN'T DO PROOF
THERE'S ASSOCIATION WITH LEWY
BODY DEMENTIA, I ALSO HAVE TO
ADMIT WE HAVE LIMITED POWER.
SOME OF THESE ALLELES ARE RARE,
AND COULD STILL PLAY A ROLE,
THERE'S A LOT OF ALLELIC
HETEROGENEITY.
, FOR EXAMPLE, IN PARKINSON'S
DISEASE, IN THE PARKINSON'S
DISEASE COMMUNITY, WHAT'S BEEN
SHOWN ON AVERAGE YOU SEE
ENRICHMENT OF DAMAGING MUTATIONS
IN PARKINSON'S DISEASE DISEASE,
IN THE LYSOSOMAL GENES.
WE SEE IT FOR A FEW OF THE GENES
BUT GLOBALLY IT JUST HASN'T BEEN
SIGNIFICANT.
IT COULD JUST BE BECAUSE IT'S
TOO RARE.
THERE'S TOO MUCH ALLELIC
HETEROGENEITY TO HAVE SUFFICIENT
POWER, BUT THOSE PATHWAYS ARE
CERTAINLY IMPORTANT IN LEWY BODY
DEMENTIA.
>> I'M BEING TOLD THAT THERE ARE
OTHER ONLINE QUESTIONS.
THANK YOU BUT WE DON'T HAVE
TIME.
>> I'M SUCH A KILL-JOY IN THIS
THING.
SONJA, THANK YOU FOR A WONDERFUL
LECTURE.
AND IN FAIRNESS TO OUR
COLLEAGUES ON VIDEOCAST, WE'RE
BEYOND THE TOP OF THE HOUR.
BUT THANK YOU AGAIN.
JUST A WONDERFULLY LUCID
PRESENTATION ON A VERY, VERY
COMPLEX SUBJECT.
>> THANK YOU SO MUCH FOR HAVING
ME.
THANK YOU.
[APPLAUSE]