>>> GOOD AFTERNOON, EVERYONE.
WELCOME TO THE WEDNESDAY
AFTERNOON LECTURE.
WE HAVE A DISTINGUISHED
PRESENTER.
RUDOLPH TANZI WHO'S TITLE COULD
HARDLY BE MORE TIMELY AS THE
BOOMERS ARE NOW HAVING THEIR
CLOCKS TICKING TOWARDS WHAT CAN
BE A PERSONAL AND ECONOMIC AND
NATIONAL DISASTER IF WE DON'T
FIGURE OUT WAYS TO PREVENT THE
ONSET OF ALZHEIMER'S DISEASE.
WE ARE HEADED FOR REAL TROUBLE
AS PRABBLE EVERYBODY IN THIS
AUDIENCE KNOWS.
AND RUDY HAS BEEN ON THE
FOREFRONT OF RESEARCH IN THIS
AREA FOR QUITE A LONG TIME.
AND SO IT'S A REAL PLEASURE AND
PRIVILEGE TO HAVE HIM COME HERE
TODAY FROM HIS POSITION AT
HARVARD AND TALK TO US ABOUT
SOME OF THE NEW THINGS THAT ARE
GOING ON AND UNDERSTANDING
CAUSES AND PROPOSING SOME NEW
THERAPEUTIC INTERVENTIONS.
RUDOLPH TANZI IS CURRENTLY THE
JOSEPH AND ROSE KENNEDY
PROFESSOR OF NEUROLOGY AT
HARVARD AND AT MASSACHUSETTS
GENERAL HOSPITAL.
I HAVE KNOWN RUDY FOR MORE YEARS
THAN PROBABLY ANY OF YOU WOULD
GUESS BECAUSE WE ACTUALLY WERE
INVOLVED IN A VERY INTENSE AND
CHALLENGING COLLABORATION
INVOLVING SEVEN LABORATORIES
BACK IN THE 1980s THAT
ULTIMATELY SUCCEEDED IN
IDENTIFYING THE GENE ARE
HUNTINGTON'S DISEASE.
I KNEW AT THAT TIME, THIS WAS
SOMEBODY WITH SPECIAL TALENTS
BECAUSE OF HIS ABILITY TO BOTH
PRODUCE LARGE AMOUNTS OF DATA
AND ALSO HAVE THE INSIGHT TO SEE
WHERE TO GO NEXT WITH WHAT WAS,
AT THAT TIME, A PRETTY
TUMULTUOUS EXPERIENCE.
THERE WAS NO GENOME PROJECT, NO
RESOURCES.
MOST TOOLS WERE PRETTY CLUNKY
AND ULTIMATELY AFTER SOME 10
YEARS, TO ACTUALLY FIND THE
CAUSE OF THAT DISEASE WAS QUITE
A CHALLENGE.
BUT RUDY WENT ON FROM THAT TO
CARRY OUT A NUMBER OF REALLY
IMPORTANT RESEARCHES AND
CONTINUES TO DO SO IN
ALZHEIMER'S DISEASE.
IT WAS RUDY WHO WAS THE FIRST
AUTHOR ON THE DISCOVERY OF THE
BETA AMYLOID GENE PROTEIN
PRECURSOR IN 1987.
AND SHOWING THAT THIS WAS A
CAUSE, ALBEIT A RARE ONE OF
FAMILIAL ALZHEIMER DISEASE.
AND THEN DEEPLY INVOLVED IN THE
DISCOVERY AND WAS A
CO-DISCOVERER OF THE SECOND TWO
FAMILIAL ALZHEIMER'S GENES.
AND AS HE WILL TELL YOU, IS
ENGAGED IN THE SEARCH FOR
ADDITIONAL ALZHEIMER'S
SUSCEPTIBILITY GENES USING THE
GENOME-WIDE ASSOCIATION STUDY
AND TRYING TO BUILD UPON THAT TO
CREATE NEW IDEAS ABOUT
THERAPEUTICS, WHICH, AS I SAID,
ARE DEBT PRACTICESLY NEEDED.
RUDY IS A GUY OF INTENSE ENERGY
AND CURIOSITY.
I SAW AN INTERESTING QUOTE FROM
HIM IN AN INTERVIEW WITH THE
NEW YORK TIMES FROM A FEW YEARS
AGO.
HE SAYS, I REALLY THINK THAT
WHAT DRIVES SCIENTIFIC DISCOVERY
IS THE QUEST TO SOLVE PUZZLES.
WHAT DROVE MY RESEARCH, HE SAID,
IS THAT SAME KIND OF FEELING
THAT DOESN'T PERMIT YOU TO PUT
THE "NEW YORK TIMES" CROSSWORD
PUZZLE DOWN.
IT'S A PURE OBSESSIVE, ALMOST
PATHOLOGICAL CURIOSITY THAT
DRIVES RESEARCH.
RECOGNIZE THAT?
HAVE YOU HAD THAT EXPERIENCE?
I THINK I HAVE AND RUDY IS
CERTAINLY A PROMOTE OR OF THE
JOY OF BEING ON A DETECTIVE
SEARCH, TRYING TO FIND AN
ANSWER, KNOWING THERE ARE A LOT
OF CLUES OUT THERE, SOME OF THEM
ARE RIGHT AND SOME ARE
MISLEADING BUT ULTIMATELY THEY
ARE GOING TO GET TO THE END OF
THE BOOK AND FIND OUT WHO DONE
IT AND HE HAS CREATED A LOT OF
ANSWERS TO THE "WHO DONE IT"
QUESTIONS ABOUT ALZHEIMER'S.
HE IS ALSO A RENAISSANCE PERSON,
AS I HAVE FOUND OUT, BY HAVING
THE CHANCE TO SEE OTHER SIDES OF
HIM IN THE LAST FEW YEARS.
ONE OF WHICH YOU CAN SEE
DEMONSTRATED HERE.
SO IF YOU HAVE BEEN WANDERING
THROUGH SHOPPING MALLS OR
AIRPORTS AND ENCOUNTERED THIS
PARTICULAR POSTER, YOU MIGHT
WONDER WHAT THE HECK IS GOING ON
THERE?
WELL, THIS IS AN EFFORT BY THE
ALZHEIMER'S ADVOCATES TO PUT
FORWARD THE IDEA THAT SCIENCE IS
COOL.
OF COURSE THE GUY WHO IS REALLY
COOL IS NOT EITHER RUDY OR ME,
IT'S THE GUY IN THE MIDDLE, JOE
PERI, THE LEAD GUITARIST FOR
AEROSMITH.
BUT WE HAD PRETTY MUCH FUN
GETTING INTO THE SAME PICTURE.
AND IF YOU GO TO YOUTUBE, AND
YOU PUNCH NIN JOE PERI, RUDY AND
FRANCIS, YOU WILL SEE OUR NEW
BIG VIDEO AND ALL OF ITS
MULTICOLORED GLORY.
AND SOME PRETTY COOL RIFFS BY
ONE OF THE MUSICIANS, THE GUY IN
THE MIDDLE, BUT THE REST OF US
WERE DOING OKAY TOO.
SO, AGAIN, GREAT PLEASURE TO
HAVE SOMEBODY WITH US WHO IS
SUCH A COMPLETE HUMAN BEING,
PLEASE JOIN ME IN WELCOMING
PROFESSOR RUDOLPH TANZI.
[APPLAUSE]
>> I THINK THAT'S THE BEST
INTRODUCTION I EVER HAD IN MY
LIFE.
THANK YOU VERY MUCH.
THAT WAS -- I DON'T HAVE TO GIVE
MY TALK REALLY.
YOU COVERED ATP AND THE ROCK
BAND.
SO IT'S A REAL PLEASURE TO BE
HERE AND THANK YOU VERY MUCH
DR. COLLINS FOR INVITING ME TO
GIVE THIS TALK.
I'M HONORED AND PRIVILEGED AND
HOPE OVER THE NEXT 45 MINUTES, I
CAN DELIVER TO YOU MOST OF WHAT
I THINK IS OPTIMISTIC AND GOOD
NEWS ABOUT ALZHEIMER'S DISEASE
AS WE DISCOVER MORE GENES, COME
UP WITH MORE PATHWAYS WHAT HAVE
IS GOING WRONG AND MOST
IMPORTANTLY, THINK ABOUT NEW
THERAPEUTICS TO NIP THIS DISEASE
IN THE BUD STAGE BEFORE IT
REALLY TAKES ROOT IN OLDER
INDIVIDUALS.
I'LL START WITH JUST SOME
DISCLOSURE, THE COMPANIES I'M
INVOLVED WITH.
SO, LET ME START WITH JUST SOME
NUMBERS.
72 SECONDS, EVERY 72 SECONDS IS
A NEW DIAGNOSIS OF ALZHEIMER'S
DISEASE IN THIS COUNTRY.
40% OF INDIVIDUALS OVER 85 ARE
BELIEVED TO SUFFER FROM
ALZHEIMER'S DISEASE, ALTHOUGH
THIS NUMBER VARIES A BIT AND BY
2015, GIVEN THE BABYBOOMERS THAT
DR. COLLINS MENTIONED, 72
MILLION HEADING TOWARDS RISK
AGE, IT'S ESTIMATED THAT IT'S
POSSIBLE FOR ALZHEIMER'S TO
START TRIPLING MEDICARE AND
MEDICAID BY 2015-2020.
400X, AND I APOLOGIZE BECAUSE
I'M AT NIH BUT HI TO DO THIS,
CORRESPONDS TO THE FACT THAT WE
SPEND 400 DOLLARS ON HEALTH CARE
AND CARING FOR ALZHEIMER'S
PATIENTS FOR EVERY THERE WE
SPEND ON RESEARCH.
IF YOU WANT TO TREND DISEASE
BEFORE IT STARTS TO TRIPLE
MEDICARE AND MEDICAID, WE NEED
TO POUR A LOT MORE INTO
RESEARCH.
IT'S A TOUGH GUNGP BUDGET RIGHT
NOW BUT IT'S A REAL BIG PROBLEM
THAT COULD HAVE HUGE
CONSEQUENCES ON HEALTH CARE IN
THIS COUNTRY OVER THE NEXT 10
YEARS FOR BABYBOOMERS.
0 CORRESPONDS TO THE NUMBER OF
DRUGS TO TREAT THE DISEASE AS
OPPOSED THE SYMPTOMS.
WHAT IS ALZHEIMER'S?
THE MOST COMMON FORM OF DEMENTIA
IN THE ELDERLY.
AGE AND PREVALENCE INCREASES
WITH EVERY DECADE AFTER 60.
WHAT GOT MY ATTENTION MANY YEARS
AGO BACK IN THE HUNTINGTON'S
DISEASE WAS FAMILY HISTORY.
AND INHERITANCE PLAYS A ROLE IN
FAMILLIA AND SPORADIC CASES
INVOLVE GENETICS.
SOME SAY -- NO, GENET 6 PLAYING
A ROLE IN ALL OF THESE CASES.
OTHER RISK FACTORS INCLUDE
TRAUMATIC BRAIN INJURY,
BASICALLY ANY INSULT TO THE
BRAIN.
NEUROVASCULAR EVENTS THAT COME
FROM STROKE, DIABETES, OBESITY
AND THE CARDIOVASCULAR DISEASE
AND SOCIAL ISOLATION, INCREASING
DATE THAT THAT SUGGESTS
LONELINESS, NOT BEING SOCIALLY
ENGAGED, CAN BE APE RISK FACTOR.
SO IT'S NOT SO IMPORTANT TO PLAY
SUDOKO, IT'S MORE IMPORTANT TO
GET OUT THERE AND GET EXERCISE
AND GET ENGAGED WITH FOLKS AS WE
GET OLDER.
AND I LIST THE RISK FACTOR AS A
GENETICIST BIRTH BECAUSE BY THE
AGE OF 120, MANY BELIEVE WE ALL
HAVE AD.
ALZHEIMER'S PATHOLOGY STARTS IN
4 YEARS OLD IN ALMOST EVERYONE.
AND AS IT ACCUMULATES, THAT IF
ALL OF US LIVE TO BE 120, YOU
WOULD AT LEAST HAVE THE EARLY
STAGES OF AT LEAST MILD
COGNITIVE IMPAIRMENT AND EARLY
STAGE AD.
WHEN WE DO GENETICS, WE GET MUCH
BETTER RESULTS ASKING WHEN YOU
GET THE DISEASE AND AGE OF ONSET
AS OPPOSED TO WHETHER YOU GET
THE DECEASED.
WHETHER HAS MORE TO DO WITH THE
LIFESPAN SUSPECT 80 YEARS OLD.
IF WE LIVE LONG ENOUGH, WE
ACCUMULATE ENOUGH PATHOLOGY THAT
EVERYONE HAS THIS DISEASE.
THE NEUROPATHOLOGY ITSELF HERE
IS SEEN MATE UP OF BETA AMYLOID
PROTEIN IN THE CORE OUTSIDE OF
NEURONS, WE DO NOT GET
ALZHEIMER'S DISEASE
WITHOUT -- YOU CAN HAVE BRAINS
FULL OF PLAQUES AND AMYLOID BUT
IF THAT DOESN'T CONVERT THEN YOU
DON'T GET DEMENTIA.
ONE OF THE BIG BLACK BOX SYSTEMS
HOW DO YOU GO FROM AMYLOID TO
THIS PATHOLOGY GIVEN THAT SEEMS
TO BE THE SEQUENCE FROM A
VARIETY OF DIFFERENT
EXPERIENCES.
SYNAPSE LOSS CORRELATES BEST
WITH DEMENTIA ACCORDING TO OTHER
STUDIES.
INFLAMMATION AND BRAIN ATROPHY
ARE ALL PATHOLOGICAL FEATURES.
AND CURRENT THERAPIES TREAT THE
SYMPTOMS.
THEY ARE BETTER THAN NOTHING.
THIS SEEMS TO BE BETTER THAN
ALONE.
-- TOGETHER THAN ALONE.
WE BELIEVE THEY PROVIDE MODEST
OR TEMPORARY BENEFIT.
WE NEED SOMETHING BETTER.
WE NEED DRUGS THAT WILL TREAT
THE DISEASE ITSELF AND THE
DISEASE PROGRESSION.
HOW DO WE GET THERE?
OUR OWN APPROACH AND BELIEF,
THIS IS NOT JUST EXCLUSIVE TO
OURSELVES, IS THAT ULTIMATELY,
THE WAY WE WILL APPROACH AD AND
OTHER AGE-RELATED DISEASES IS
PHARMACOGENETICALLY.
THE IDEA IS TO FIND ALL OF THE
GENES INVOLVED IN CONFERRING
THIS TO THE DISEASE, COME UP
WITH ALGORITHMS THAT PREDICT THE
DISEASE EARLY AND MAKE SURE SOME
ARE GENETIC AND PSYCHOLOGICAL
AND ADD PRIVACY LAWS IN PLACE.
WE STILL NEED MORE TO PROTECT
AGAINST LONG-TERM CARE AND
LICENSURE, NOT JUST HEALTH
INSURANCE AND UNEMPLOYMENT.
SO HOPEFULLY THAT WILL COME AND
THEN IF ONE IS AT HIGHER RISK,
WE NEED EARLY DETECTION.
WE NEED TO FOLKS YOU NEED TO BE
MORE VIGILANT BECAUSE OF YOUR
RISK.
YOU NEED TO HAVE AN MRI OR CHECK
FOR BIOMARKERS MORE OFTEN JUST
LIKE SOMEONE WITH A FAMILY
HISTORY OF COLONOSCOPY MIGHT
HAVE TO GO THROUGH THAT
EXPERIENCE MORE OFTEN.
I'M OVER 50 SO I CAN SAY IT'S A
WONDERFUL EXPERIENCE.
SO YOU MAY NEED TO BE MORE
VIGILANT IF YOU'RE RISK IS
HIGHER.
ASK THEN THESE GENES TEACH US
HOW TO PREVENT THE DISEASE.
THIS IS THE MOST IMPORTANT
THING.
THE POLYP PEOPLE.
SO THE IDEA IS THAT WHAT WE WANT
TO DO OVER THE NEXT DECADE OR SO
IS NOT NECESSARILY CURE
ALZHEIMER'S.
WE WANT TO CURE IT.
BUT I THINK A MORE REASONABLE
AND ATTAINABLE GOAL IS TO
ERADICATEA2
WE ERADICATE POLIO WITH A
VACCINATION.
TO TRY TO ERADICATE BY EARLY
PREDICTION, EARLY DETECTION AND
EARLY PREVENTION.
THIS COUNTS FOR ANY OF THE BIG
AGE-RELATED DISEASES.
NOW JUST A BRIEF HISTORY OF
GENETICS.
I'LL TOUCH ON RESPONSIVE THESE
THINGS.
IT STARTED IN 1984 WITH GEORGE
GLENNER WHO DESERVED THE AMYLOID
BETA PROTEIN AND PUBLISHED THESE
PAPERS CONFIRMED BY COLIN A YEAR
LATER IN 1985.
THIS ALLOWED MY GROUP AND OTHERS
IN 87 TO ISOLATE THE GENES TO
AMYLOID TO BE RENAMED THE
AMYLOID BETA PROTEIN PRECURSOR
BUT IT WASN'T UNTIL 1990 THE
FIRST PATHOGENIC MUTATIONS WERE
FOUND IN APP FIRST IN A CEREBRAL
AMYLOID DOSEIS FAMILY AND THEN
FOLLOWED BY ALZHEIMER'S
FAMILIES.
IN 92, THE FIRST AND ONLY
ESTABLISHED LATE ONSET JEAN WAS
FOUND AT DUKE AND IN 1995, WE
AND OTHERS WORKING WITH OTHERS,
FOUND 1 AND 2 WHICH ALSO CALLED
THE EARLY ONSET FORM OF AD.
IN 2007, NOW THERE IS A BIG GAP
BETWEEN 95 AND 2007.
HUNDREDS OF CANDIDATE GENES WERE
TESTED BY LABS ALL OVER THE
WORLD LOOKING FOR ASSOCIATION
WITH AD SIMILAR TO WHAT WAS
FOUND FOR APE.
THERE WERE A LOT OF YESES AND
NOS AND REPLICATIONS.
SO BER TRAM AND I PUT TOGETHER
THIS DATABASE WHICH NOW PROVIDES
THE DATABASE AND METANALYSIS FOR
ALL THE PUBLISHED LITERATURE ON
THE UPDATED BASIS ONLINE AND
FREELY AVAILABLE.
IN 2008, USING A FAMILY-BASED
GWAS, WE PUBLISHED THE FIRST
FOUR GENES THAT SHOWED
GENOME-WIDE SIGNIFICANT.
I'LL TELL BUT THIS.
AND THIS WAS FOLLOWED A YEAR
LATER IN 2009 BY A GROUP THAT
SERVED THE FIRST GENOME-WIDE
SIGNIFICANT GENE USING A CASE
CONTROL FORMAT AND IF HI 2011
HERE, WE WILL BE HEARING SOON
ABOUT THE AMERICAN CONSORTIUM
FROM NIA AND EXCITING RESULTS
COMING FROM THEM.
BUT THAT WILL BE OUT SOON AND
YOU'LL HEAR ABOUT THAT LATER.
SO, WHAT HAVE THE GENES TAUGHT
US?
THE EARLY ONSET GENES HAVE
TAUGHT US THAT ABATA IS THE
CENTRAL FOCUS OF THIS DISEASE.
IF YOU LOOK AT THE EARLY ONSET
GENES, THE MAJORITY OF THE
MUTATIONS IN THESE GENE OVER 200
OF THEM, INCREASE THE RATIO OF A
BETA 42 OVER 40.
42 HAS EXTRA ON THE C TERMINUS.
SOME LIKE DUPLICATIONS, YOU HAVE
THREE COPIES OF 21, THEY NEED
JUST MORE PRODUCTION OF A BETA.
THERE IS ONLY ONE MORE MUTATION
THAT LEADS TO INCREASED
MUTATION.
SO SOMETIMES YOU HEAR EARLY ON
SET GENES INCREASE A BETA
LEVELS.
THAT'S NOT TRUE.
WITHOUT DOING A LOT TO BETA
PRODUCTION, YOU SKEW THAT RATIO,mHKmy
NORMALLY 42 IS 10%, YOU HAVE A
LITTLE BIT MORE, THAT DRIVES THE
AGGREGATION.
IT'S TOUGH FOR THE BRAIN TO
CLEAR AGGREGATIVE A BETA VERSUS
MONMERIC A BETAÉCál
 PEPTIDE.
PPOE IS INVOLVED WITH THE
CLEARANCE.
INSTEAD OF HAVING PEN
TRIMUTATIONS THE EARLY ONSET
GENES, APOE IS A HUGE RISK
FACTOR THAT DOESN'T GUARANTEE
THE DISEASE, AT LEAST NOT GIVEN
OUR CURRENT LIFESPAN.
MAYBE IF YOU LIVED TO 120, THIS
BECOMES A FULLY PENETRANT
VARIANT.
SO THIS IS THE SCHEME THEN THAT
COMES OUT IF THE FIRST FOUR
JEANS, APP IN ORDER TO MAKE A
BETA YOU HAVE TO HAVE BETA AND
GAMMA TO RELEASE IT.
ALPHA IS IN THE MIDDLE AND YOU
CONCLUDE BETA PRODUCTION.
ENCODE THE ACTIVE SUBUNITS AND
THE EARLY ANTIGEN PROVIDES
SUBSTRATE.
AND THEN THE SUBSTRATE AND
ENZYME ON EITHER SIDE INCREASES
RATIO AND APOE TRIES CLEAR IT
FROM THE BRAIN AS IT AG GATES,
IT BECOMES MORE DIFFICULT.
AGGREGATION OCCURS FIRST AT THE
LIGMERS, DIMERS DIMERS AND TRIMERS AND
DECAMERS.
THESE ARE LIGMERS PROBABLY MORE
DANGEROUS THAN THE PLAQUES
BECAUSE THEY ARE FREE FLOATING
AND WHEN THEY BUILDUP IN
SYNAPSES THEY OCCUR IN
NEUROTRANSMISSION AND MANY
BELIEVE THIS IS THE BATTLEGROUND
IN ALZHEIMER'S.
LIGMERS CLUMPS THE SYNAPSE
ITSELF.
EVENTUALLY THIS WILL FORM FLAKS.
THESE ARE NOT SAFE.
-- PLAQUES.
THEY CAUSE OXIDATIVE STRESS DUE
TO INFLAMMATION AND SOMEWHERE IN
THIS PROCESS, EITHER FROM
PLAQUES OR ODATIVE STRESS,
TANGLES FORM AND THE BIGGEST
BLACK BOGS -- BLACK BOX IN THIS
DISEASE.
HOW DO YOU GO FROM AMYLOID TO
TANGLES?
HOW IS IT WE CAN HAVE MAYBE LIKE
25 CASES AT MASS GENERAL, BRAINS
FULL OF AMYLOID, NO DEMENTIA,
BECAUSE THERE ARE NO TANGLES?
SO OBVIOUSLY SEQUENCING THESE
PEOPLE FOR LACK OF ANYTHING
TOLLS DO RIGHT NOW, WE NEED,JÑR1&#] TO
FIGURE OUT HOW AMYLOID
TRANSLATES INTO TANGLES.
THIS IS A BIG QUESTION I'LL GET
TO LATER O WE DON'T KNOW YET.
BUT WITHOUT TANGLES, YOU DON'T
HAVE DISEASE.
NOW THESE FOUR GENES ACCOUNT FOR
MAYBE 30-50% OF THE GENETIC
VARIANTS OFiozí4YE1VQ#%P](2
GENES TO BE FOUND AND MANY OF US
US ALL AROUND THE WORLD ARE
ATTEMPTING TO FIND THESE OTHER
ALZHEIMER GENES.
LIKE I TOLD YOU EARLIER, WE ARE THE WORL
D ARE
ATTEMPTING TO FIND THESE OTHER
ALZHEIMER GENES.
LIKE I TOLD YOU EARLIER, WE ARE THE WORL
D ARE
ATTEMPTING TO FIND THESE OTHER
ALZHEIMER GENES.
LIKE I TOLD YOU EARLIER, WE ARE THE WORL
D ARE
ATTEMPTING TO FIND THESE OTHER
ALZHEIMER GENES.
LIKE I TOLD YOU EARLIER, WE ARE THE WORL
D ARE
ATTEMPTING TO FIND THESE OTHER
ALZHEIMER GENES.
LIKE I TOLD YOU EARLIER, WE ARE THE WORL
D ARE
ATTEMPTING TO FIND THESE OTHER
ALZHEIMER GENES.
LIKE I TOLD YOU EARLIER, WE ARE PROTEIN 
POLYMORPHISMS.
IT'S A SYSTEMATIC DISPLAY OF ALL
STUDY DETAILS.
660 GENES ARE COVERED.
OVER 3,000 SNPS AND MOST
IMPORTANTLY, WHEN THE SNPS, A
SINGLE NUCLEOTIDE POLYMORPHISM
OR COMMON GENE VARIANT HAS BEEN
TESTED IN AT LEAST FOUR
INDEPENDENT SAMPLES, AND THIS IS
ALL CASE CONTROLLED HERE, NOT
FAMILY BASED.
MY LAB IT'S FAMILY BASED BUT
MOST OF THE DATA IN THE FIELD
ARE CASE CONTROLLED STUDIES
WHERE YOU APPEAR RANDOM CASES
AND CONTROLS.
SO IF IT'S SNP FOR COMMON
VARIANTS HAVE BEEN TESTED IN
FOUR INDEPENDENT SAMPLES, THEN
YOU DO METANALYSIS TO SAY HOW
DOES IT LOOK?
DOES IT HOLD UP?
AND OF THESE 3,000 SNPS, OVER
300, 10% OF THEM, HAVE BEEN
TESTED IN FOUR INDEPENDENT
SAMPLES, SOMETIMES IN THE SAME
PAPER.
OF THOSE 300, 42 OF -- OR OF 38,
USE SIGNIFICANT RESULTS.
IT'S A MOVING TARGET.
BECAUSE WE ARE UPDATING THIS ALL
THE TIME.
IF YOU WENT TO THE WEBSITE, YOU
THINK IT'S JUST THE 42 GENES,
RANK ORDERED, ACCORDING TO
SIGNIFICANTS OF ASSOCIATION AND
YOU CAN GET METANALYSIS.
APOE IS NUMBER 1 AND SO ON.
I'LL MENTION SOME OF THESE
THROUGHOUT THE TALK BUT NOT
HERE.
NOW WHAT IS REALLY IMPORTANT TO
ADD IS OF THESE 42 GENES, THE
EFFECTS ON AD RISK WHICH IS
COMMON VARIANTS ARE APPARENT.
AND SMALL.
INCREASES RISK BY 20%.
1.2 FOLD INCREASE IN RISK.
AND SOME PEOPLE SAYS, WHO CARES?
WHAT'S THAT DOES THAT MATTER?
THESE NUMBERS PROBABLY DON'T
MEAN MUCH BUT THEY TELL YOU WHAT
WE NEED TO DO NEXT.
APOE IS THE EXCEPTION.
NOT ONLY THE EXCEPTION IN
ALZHEIMER'S BUT THE EXCEPTION IN
COMMON HETEROGENOUS GENETIC
DISEASE BECAUSE E4 INCREASES AD
RISK BY 4-12 FOLD.
SO HUGE EFFECT.
THIS IS IN A CLASS OF ITS OWN
HERE.
WHAT DO YOU DO WITH THIS?
HOW DO WE DEAL WITH THEM?
IF WE PLOT THESE OUT HERE WHERE
WE HAD EFFECT SIZE, PENETRANTS
ON THE Y AXEIS AND THIS IS HOW
FREQUENT THE ALLELE IS, SO THIS
IS VERY RARE AND THIS IS A
COMMON ALLELE OF A VARIANT, AND
WHAT WOULD HAPPEN IS APP AND THE
EARLY ONSET GENES WOULD BE HERE,
FULLY PENETRANT MUTATIONS
EXCEEDINGLY REAL.
THESE MUTATIONS TOGETHER, ALL
200, MAYBE ACCOUNT FOR ONE OR 2%
OF THE AD.
APOE WOULD BE HERE.
NOT FULLY PENETRANT.
INCREASING RISK 4-12 FOLD.
A VERY COMMON VARIANT.
THE E4 VARIANT IS IN 20% OF THE
POPULATION.
THE REAL SEQUENCE IS OVER 10%.
THAT'S A COMMON VARIANT.
A PRETTY BIG EFFECT ON RISK BUT
NOT FULLY PENETRANT.
BUT ALL OF YOUR GWAS HITS, ALL
YOUR ALZGENE HITS ARE DOWN HERE.
COMMON VARIANTS WITH TIMING
EFFECTS, ODDS RATIOS OF 1.1 FOR
RISK OR TO 1.2 5.
NOW, THIS MODEL WAS REALLY
POPULAR IN THE 90's AND STILL
I THINK THE REIGNING PARADIGM.
THE IDEA THAT THE COMMON
DISEASE, COMMON VARIANTS LIKE
APOE FOR AD AND FOR RARE DISEASE
LIKE EARLY ONSET FAMILIAR YARR
DISEASE, THERE ARE RARE
MUTATIONS.
AND SO IT'S A GENETIC DICHOTOMY
BUT THISICALS INTO QUESTION
LATELY.
AND I THINK YOU HAD DR. DAVID
GOLDSTEIN SPEAK HERE FROM DUKE
RECENTLY WHO SHOWED HIS
INTERESTING WORK OF, YOU KNOW,
THE COMMON VARIANTS WHO USE THIS
ARE REALLY OLD.
THEY TAG ANCESTRAL HAPLOTYPES
THAT YOU REALLY HAVE TO DIG IN
AND YOU MIGHT FIND WHAT IS
REALLY DRIVING THIS ASSOCIATION
ARE RARE MUTATIONS THAT ONLY
OCCURRED 10,000 YEARS AGO.
SO, IS THIS REALLY A CASE OF
DOZENS OF COMMON VARIANTS WITH
TIMING EFFECTS ALL CONSPIRING TO
CAUSE THE DISEASE TOGETHER WITH
THE ENVIRONMENT OR COULD IT BE
THESE SNPS TAGGING THE HAPLOTYPE
BLOCKS THAT HAVE MANY DIFFERENT
RARE VARIANTS IN MUTATIONS WITH
STRONGER BIOLOGICAL EFFECTS?
HERE IS WHAT GOLDSTEIN DID.
LET'S PRETEND WE DON'T KNOW THE
CAUSE IS RARE FOR SICKLE-CELL
ANEMIA.
THEY DID A GWAS.
THEY CAME UP WITH 179 SNPS
COVERING 2.5 MEGABASES ALL OF
WHICH ARE GENOME-WIDE
SIGNIFICANT WITH SMALL EFFECTS
ON RISK.
WE KNOW THAT'S NOT TRUE.
I MEAN, ALL OF THESE GENES HAVE
COMMON VARIANTS THAT CONSPIRE
TOGETHER TO CAUSE THIS DISEASE.
NOT THE CASE.
WHAT HAPPENED IS THE HIGHEST P
VALUES ARE HERE AND IF YOU GO
DOWN IN THIS CLUSTER HERE YOU
SEE HP R AND A RARE MUTATION
HERE AND IT DRIVES THIS APPARENT
ASSOCIATION, UNOFFICIAL
ASSOCIATION W THESE COMMON
VARIANTS THAT ARE VERY OLD
TAGGING THESE ANCESTRAL
HAPLOTYPES WITH APPARENTLY SMALL
EFFECTS.
IT'S ARTIFICIAL.
WE NEED TO DO THE GWAS IF YOU
DIDN'T KNOW.
YOU WOULDN'T KNOW WHERE THE
SEQUENCE IS AND FIND THE RARE
MUTATION THAT IS MUCH MORE
RECENT.
SO LET ME GIVE YOU AN EXAMPLE OF
WHAT WE DID IN ALZHEIMER'S
DISEASE USING THE SAME MODEL AND
IT INVOLVES ALPHA -- I MENTIONED
THAT APP, IF SECRETES.
BUT A BETA GETS CUT IN HALF AND
SO NOW YOU CONCLUDE THE
PRODUCTION.
AND WE KNOW FROM THE WORK OF
SEVERAL FOLKS THAT ADAM KEN IS
THE MAJOR SERETASE IN THE BRAIN.
THERE IS ALSO ADAM 9 AND 17.
RECENTLY ADAM 9 IS THE MAIN SEEK
RETAZE IN THE BRAIN.
SO WE LOOKED AT ADAM 10S IS A
CANDIDATE JEAN AND WE HAD GWAS
RESULTS ON IT AND SAW A LOT OF
SNPS IN ADAM 10 SHOWED P VALUES
THAT WERE NEVER PASS FOR
CORRECTION, THESE WERE NOT
GENOME-WIDE SIGNIFICANT BUT THEY
WERE SHOWING ASSOCIATION IN THIS
ONE BLOCK AND THIS ONE INTRON OF
ADAM 10.
SO WE SAID, LET'S TEST THIS.
WE PUT IT OUT THERE AND IF YOU
GO TO ALZGENE TODAY, WILL YOU
SEE ADAM 10 IN THE MIDDLE OF THE
LIST.
IT IS METANALYSIS SIGNIFICANT
AND MADE THE GRADE.
THIS IS RIGHT HERE IN THE MIDDLE
AND HERE IS YOUR SNP THAT IS
PRETTY COMMON.
HERE IS A METANALYSIS RIGHT HERE
AND IT INCREASES THE INTRONNIC
SNP FOR AD BY 1.15 FOLD.
SO A TINY EFFECT AGAIN.
COMMON VARIANT, TINY EFFECT.
WHAT WE DID IS DUG IN AND WE
FOUND THE FAMILIES IN WHICH THIS
SNP WAS MAINLY -- WHEN WE DO
FAMILY-BASED ASSOCIATION, NOT
CASE CONTROL, SO WE CAN LOOK AND
SAY, WHAT FAMILIES ARE REALLY
DRIVING THIS ASSOCIATION?
WHERE IS THE SNP SEGREGATING
BEST WITH THE DISEASE?
IT IS LATE ONSET BUT WE HAVE
MULTIPLE EFFECTS IN LATE ONSET.
SOMETIMES 2-4, SOMETIMES 6-7.
WE RESEQUENCED SOME FAMILIES AND
FOUND TWO MUTATIONS, Q178, AND
R181G.
THESE ONLY OCCURRED IN SEVEN
FAMILIES OUT OF 1,04.
THEY WERE PRETTY BIG FAMILIES.
AND ALL OF THESE FAMILIES WERE
70 YEARS OLD.
THE MUTATIONS WERE PRESENT IN
ALL ABOUT 2(
BUT AMONG UNAFFECTED, WEW
FOUND ONE UNEFFECTED INDIVIDUAL.
THIS SUGGESTED THESE COULD BE
THE FIRST RARE HIGHLY PENETRANT
OUGHT SOMAL DOMINANT-?_
 MUTATIONS
FOR LATE ONSET DISEASE.
HERE IS THE MUTATIONS IN ADAM
10.
SO IT HAS A PRO DOMAIN HERE THAT
HAS TO BE CLEAVED OFF TO
ACTIVATE THE ENZYME.
HERE IS THE POSITIVE CONTROL.
WE PUBLISHED THIS
'09 AND SHOWED IT IN RETRO IN
CELL-BASED STUDIES THAT EACH
MUTATION DECREASED APP BY
GREATER THAN 70%.
HERE IS WILD TYPE.
HERE IS MUTATION 1.
HERE IS MUTATION 2.
AND JUST FOR COMPARISON, THE
ARTIFICIAL DOMINANT NEGATIVE.
THESE IMPAIR ADAM 10 ACTIVITY ON
APP.
BUT IT'S IN-VITRO SO WE DIDN'T
SQUAWK TOO LOUD.
WE SAID, LET'S DO THE IN-VIVO
STUDY AND MAKE TRANSGENICS.
I SHOULD STATE IT HAD EFFECTS ON
A BETA AS YOU WOULD EXPECT.
WE MADE TRANSGENICS AND THIS IS
WHAT WE SAW.
WE MILD WILD TYPE ADAM 10.
THE FIRST MUTATION, THE SECOND
MUTATION, HERE IS THE DOMINANT
NEGATIVE.
THE FIRST THING YOU CAN SEE IS
ADAM 10 GETS CLEAVED, CLEAVES
ITSELF, TO CREATE A CTF, A C
TERMINAL FRAGMENT.
HERE IS THE WILD TYPE ADAM 10
AND THERE IS THE C TERMINUS
FRAGMENT.
BUT THE DOMINANT NEGATIVE
ARTIFICIAL MUTATION MICE, YOU
DON'T SEE IT AND AT Q178 YOU
DON'T SEE IT AND IT'S
DRAMATICALLY LOWER.
SO THE FIRST THING YOU NOTICE,
MORE THAN INFECTING IN-VIVO ON
APP WAS THAT THIS CTF IS
DISAPPEARING IN THE LOWER.
NOW DATA SUGGESTING THAT THIS IS
ACTUALLY PROCESSED INTO AN ICD,
INTRACELLULAR DOMAIN THAT GOES
TO THE NUCLEUS AND HAS
TRANSCRIPTIONAL ACTIVITY AND
HELPS TO REGULATE INCREASED ADAM
10 ACTIVITY AND APP.
THAT'S A STORY JUST STARTING TO
EMERGE.
WE DON'T HAVE THE FULL MOLECULAR
MECHANISM BUT WE CAN SEE THE
EFFECTS.
THIS IS WHAT WE SEE THAT IS MOST
IMPORTANT.
THIS IS THE BETA SERETASE
PRODUCED APP SO WHEN IT CUTS
APP, YOU RELEASE AN ECTODOMAIN.
AND YOU CAN SEE IN THE
NONTRANSGENIC, HERE IS THE APPS
BETA.
WHEN YOU OVER EXPRESS ADAM 10
WILD TYPE, APPS BETA GOES AWAY
BECAUSE YOU'RE SHIFTING APP INTO
THAT PATHWAY.
BUT WHEN YOU OVEREXPRESS AND YOU
HAVE THE MICE MAKING THE T170H
MUTATION OR THE ARTIFICIAL
DOMINANT NEGATIVE, APPPS BETA
PERSISTS.
ITS EXCESS TIME YOU'RE PUTTING
INTO THESE MICE, BECAUSE BECAUSE
IT'S MUTATED, IT'S NOT DRIVING
APP AS MUCH.
SO YOU STILL SEE A GOOD AMOUNT
OF APPS BETA.
AND THEN THIS TRANSLATE INTO A
BETA.
SO IT HAD BEEN PUBLISHED A FEW
YEARS AGO THAT IF YOU TAKE A
TRANSGENIC AB MOUSE.
WE CROSSED THE ADAM 10 MICE WITH
2576 MICE.
AND THIS IS ALL PUBLISHED BY THE
WAY.
SO WE CAN SEE THAT IN THE 2576
MICE, THE A BAIT AT MICE GO
DOWN, THE ADAM 10 PROTECTS.
THAT CONFIRMS WHAT WAS
PUBLISHED.
WHEN YOU PUT IN THE MUTANT LATE
ONSET MUTANTS, YOU SEE NO
PROTECTION.
A BETA IS NOT BEING REDUCED.
IT'S NOT DOING THE JOB OF WILD
TYPE AND BRINGING A BETAA BACK
NOW AND THE DOMINANT NEGATIVE
MUTATION MICE, A BETA GOES UP.
SO THIS SAYS TO US THAT WHAT IS
HAPPENING WITH MUTANT ADAM 10 IS
YOU ARE JUST NOT GETTING THE
PROTECTION THAT YOU GET FROM
WILD TYPE ADAM 10 AND THIS WOULD
BE CONSISTENT WITH THE IDEA OF A
LATE ONSET DISEASE NOT STRIKING
UNTIL 70 YEARS OLD.
SO BASED ON THIS, WE PROPOSE
GIVEN WE NOW HAVE DEMONSTRATED
PATHOGENIC MUTATION WITH ADAM
10, IT COULD BE SEEN GOING
BEYOND CANDIDATE GENE BECAUSE WE
HAVE THE MUTATIONS HERE AS I
JUST DESCRIBED TO YOU.
AND NOW WITH IN-VIVO VALIDATION.
THIS IS THE TYPE OF WORK WE NEED
TO DO.
IT'S A LOT OF WORK TO GET TO A
NEW GENE WHERE YOU SEE THAT IS
AN AD GENE BEYOND JUST
REPLICATION OF GWAS RESULTS.
BUT YOU NEED TO START WITH GWAS
RESULTS TO GET THERE.
SO ADAM 10 WAS HERE.
INITIALLY A COMMON VARIANT AND
EN 18 TRON WITH A TINY EFFECT ON
RISK -- AN INTRON.
THIS IS THE ONLY WAY I LEARNED
TO DO THIS.
NOW IT'S HERE.
WE CAN MOVE ADAM 10 INTO THIS
CATEGORY.
THE REAL STORY WAS RARE
MUTATIONS LIKE A STRONG AFFECT
IN TERMS OF PENETRANTS AND THE
GWAS ARTIFICIALLY SHOWING THE
RESULTS OF THOSE TWO MUTATIONS
DRIVING THIS ASSOCIATION WITH
THE ANCESTRAL HAPLOTYPE THAT
CONTAINS THEM.
OUR GOAL IS TO KEEP DOING THIS
AND SEE HOW MANY OF THESE GENES
INSTEAD BEING COMMON VARIANTS
WITH SMALL EFFECTS, ARE POINTING
TO RARE MUTATIONS WITH STRONG
AFFECTS.
SO, THERE ARE MANY DIFFERENT
GWAS GOING ON.
OF COURSE I WANT TO EMPHASIZE
THE GWAS IS A BEGINNING NOT AN
END.
IT'S JUST TELLING YOU WHERE TO
LOOK.
TELLS YOU WHERE TO SEQUENCE.
DON'T BELIEVE THESE ODDS RATIOS
OF 1.1 WITH A RANDOM AND CHRONIC
SNP.
IT SAYS SEQUENCE THAT GENE, DO
THE WORK.
DO THE BILEY AND VALIDATE
IN-VITRO AND IN-VIVO.
THAT'S HOW YOU GET THERE NO
MATTER HOW LONG IT TAKES.
THIS IS THE GWAS STUDIES SHOWN
HERE IN THE MANHATTAN PLOT AND
THIS IS FROM A PAPER WE JUST
PUBLISHED AT THE END OF LAST
YEAR IN NEURON, A REVIEW OF GWAS
STUDIESES AND SUMMARIZES SOME OF
THE HITS.
SO FROM OUR FAMILY-BASED GWAS
FROM THE FIRST FOUR -- THESE ARE
GENOME-WIDE SIGNIFICANT HITS.
THAT MEANS THAT ALL THE GENES
SHOWN HERE WHEN YOU CORRECT FOR
HOW MANY TESTS AND COMPARISONS
YOU GET, YOU MULTIPLY THE P
VALUE TIMES THAT YOU DO A
IMPRESSION AND THEY STAYED
SIGNIFICANT.
SO THE FIRST FOUR THAT STAYED
SIGNIFICANT CAME FROM OUR
FAMILY-BASED GWAS IN '08.
THE LOCUS WAS NO APPARENT GENE.
THE POST SYNAPTIC DENSITY GENE
AND ATXN1 WHICH I'LL TALK MORE
MORE AND THEN AFTER CASE CONTROL
GENOME-WIDE SIGNIFICANT HITS
CAME OUT.
PCDHX11 AND THEN THE EUROPEAN
CONSORTIUM THAT PUT OUT THESE
FOUR HITS, CLU CLUSTERING.
PICALM AND CR1 AND BIN1 CAME UP
LATER FROM B.
AND THEN PEGGY PUB PUBLISHED
MTHFDL1.
SO THESE ALL OF THESE GENES
SHOWED GENOME-WIDE SIGNIFICANT
AND DESERVE TO BE LISTED AS THE
STRONGEST CANDIDATES WE HAVE AND
THERE ARE FIVE MORE COMING
YOU'LL HEAR ABOUT AT SOME POINT
FROM THE NIA, ALZHEIMER'S
DECEASE GENETIC CONSORTIUM AND
EUROPEAN CONSORTIUM.
I PUT STARS AROUND THESE BECAUSE
THESE HAVE THE STRONGEST LEVELS
OF REPLICATION, CD33 THE ONLY
ONE THAT HAS REPLICATION OF BOTH
FAMILY-BASED AND CASE CONTROL
STUDIES.
NOW LET ME TELL YOU ABOUT
ATTACKS IN 1.
IT CAUSES ATAXIA IF IT CONTAINS
A GLUTAMINE REPEAT.
WE LOOKED RIGHT AWAY AT THE
GLUTAMINE REPEAT AND SAW NO
EFFECTS.
IT WAS NEITHER BIGGER OR
SMALLER.
WE'RE STILL SEQUENCING ATTACKS
IN TO FIND INDICATIONS.
BEFORE YOU HAD MUTATIONS, YOU
COULD DO FUN THINGS LIKE DRIVE
UP EXPRESSION OR KNOCK IT DOWN
AND SEE WHAT HAPPENS FOR EXAMPLE
TO A BETA.
NOW, WHEN WE STARTED TO DO THIS
WORK, WE READ A PAPER THAT I
THINK THE ALZHEIMER'S FIELD KIND
OF MISSED, WHERE KNOCK-OUT MICE
WITH ATAXIN1 HAVE LEARNING
DEFICITS AROUND THE SAME TIME AS
THE 2576 MUTATION MICE.
AND LIKE THOSE MICE -- WE
THOUGHT THIS WAS INTRIGUING AND
WE GOT THE ATXN1 KNOCKOUT MICE
FROM HUDAH.
FIRST WE HAD DONE JUST
EXPERIMENTS IN PRIMATE NEURONS
WHERE YOU KNOCK DOWN ATXN1.
AND WE WERE SURPRISED TO SEE A
DRAMATIC AFFECT ON A BETA
LEVELS.
THAT 40 AND 42 HAD DRAMATICALLY
KNOCKED ATXN1 ONE DOWN.
IF WE JUST OVER EXPRESSED IT, IT
CAN DROP A BETA DOWN.
IT GOES IN BOTH DIRECTIONS.
AND THAT IS PUBLISHED.
SO, WE GET THE KNOCKOUT MICE AND
WHAT WE COULD SEE IS THE
PROBABLE EXPLANATION FOR THIS
AND WHAT WE SEE IS THAT IN THE
KNOCKOUT MICE YOU GET A PRETTY
DECENT INCREASE IN BASE 1
LEVELS.
BASE 1 IS THE BETA SERETASE.
AN ENZYME THAT MAKES A BETA.
THE RATE LIMITING STEP AND IF
YOU THINK THAT'S -UE CAN SEE
THERE IS INCREASE IN BASE 1
LEVELS.
IT CORRESPONDS IN INCREASE IN
SEE YA TAZE AND WE HAVE TO
KNOCKOUT WITH AD MICE BECAUSE
YOU DON'T GET A LOT OF A BETA IN
THE MICE WITHOUT HUMAN APP SO
THOSE CROSSES HAVE BEEN DONE AND
NOW WE ARE LOOKING AT A BETA
LEVELS IN THE ATXN1 MICE.
SOMEHOW ATXN1 CONTROLLED A BETA
LEVELS AT THE LEVEL OF
CONTROLLING BETA SERETASE LEVELS
AND WE ARE EXPLORING NOT JUST
MUTATIONS BUT TRYING TO FIGURE
OUT HOW IT IS DOING THIS.
WE KNOW IT'S NOT
TRANSCRIPTIONAL.
BASED ON THESE CHANGE, WE KNOW
IT'S NOT HALF-LIFE.
BASE ONE DEGRADATION DOESN'T
CHANGE.
SO SOMEWHERE IN THE MIDDLE
EITHER AT THE TRANSLATIONAL
LEVEL, PERHAPS AT THE SPLICING
LEVEL, SO WE ARE LOOKING AT THIS
NOW TRYING TO FIND MUTATIONS.
BASED ON THE GRAY EXAMPLE OF AN
UNBIASED GWAS GIVING AWE A GENE
YOU WOULD NEVER HAVE BELIEVED
COULD CAUSE AD.
AND THEN SEEING ANOTHER WAY TO
CONTROL BETA SEE YA DAYS LEVELS.
SO -- SERETASE LEVELS.
THIS IS WHY YOU NEED TO DO GWAS
AND DO DATA BIOLOGY AND FIND
MUTATIONS AND KEEP GOING.
THIS HAS BEEN A LIST OF SOME
OTHER GENES THAT ARE COMING OUT
OF GWAS AND AILS GENE AND HOW I
FORCED THEM TOa,éXv FIT INTO THE
AMYLOID PATHWAY SHOWN HERE AND I
WANT TO DRAW YOUR ATTENTION TO
THIS RED BOX WHICH IS
INFLAMMATION AND INNATE
IMMUNITY.
REMEMBER THE BRAIN DOESN'T HAVE
ANTIBODIES AND T-CELLS AND
B-CELLS.
IT USES THE OLD-FASHIONED INNATE
IMMUNITY SYSTEM MEANING IF THERE
IS A PROBLEM, ANY INSULT
WHATSOEVER, INFECTION,
NEUROTOXINS, STROKE, TRAUMATIC
BRAIN INJURY, TURN ON THE INNATE
IMMUNE SYSTEM AND THIS IS HOW
THE BRAIN DEALS WITH
NEURODEGENERATION.
YOU ALSO MAKE ANTIMICROBIAL
PEPTIDES, ANTIBODIES OF THE
INNATE IMMUNE SYSTEM.
AND I'LL SHOW YOU IN A MOMENT A
BETA LOOKS FOR ALL INTENSE
PURPOSES TO BE A ANTIMICROBIAL
PEPTIDE.
THIS MAY EXPLAINS WHY A BETA IN
MANY DIFFERENT EXPERIMENTS IS
TURNED UP DURING INFLAMMATION
AND INJURIESc
LD
IMMUNE SYSTEM IS TURNED ON.
THIS SLIDE MAKES THE POINT THAT
MANY OF THE NEW GENES WE ARE
FINDING, STARTING WITH PD33,
CR1, CLU AND ALL OF US HERE,
MANY JEANS IN THE INNATE
IMMUNITY PATHWAY ARE SHOWING UP
IN GWAS AS A GROWING CONTRIBUTE
OR TO AD GENETICS.
SOME OF THESE GUYS WE WANTED TO
SHOW GENOME-WIDE SIGNIFICANTS
AND METANALYSIS SIGNIFICANCE.
CLUSTERING, IT'S A COMPETENT
ACTIVATION.
CR1, AND CD33 THE REGULATOR THAT
DETERMINES ONE OF THE
GENES -- WHETHER THE INNATE
IMMUNE SYSTEM WILL BE KICKED ON
OR NOT.
CD33 IS ACTIVATED, THEN THE
INNATE IMMUNE SYSTEM IS
INHIBITED.
SO THIS WAS THE ONE THAT CAME
OUT OF OUR SCREEN.
AND THEN YOU HAVE OTHERS.
YOU HAVE ON THE INFLAMMATION
SIDE, HAVE YOU CYTOKINES,
CHEMOKINE RECEPTOR 2.
IL33, IL1B AND TNF AND IL33.
SO THESE GENES START TO TURN UP
AND IT IT MEANS IN THE PAST WE
SAID JUST PAY ATTENTION TO
INFLAMMATION.
WELL, CHICKEN OR EGG?
IS IT REALLY PART OF THE
DISEASE?
WE HAVE TO LOOK AT THE BEGINNING
SIDE, INNATE IMMUNITY, HOW THE
INNATE IMMUNE SYSTEM IS
TRIGGEREDDERED IN RESPONSE TO
INJURY AS WELL.
SO AS WE GO THROUGH THESE GENES,
THERE ARE MANY MORE GENES COMING
IN PUBLICATIONS TO COME ON GWAS
AS WELL.
SO THIS IS THE MODEL THEN THAT
WE DEVELOPED BASED ON WHAT WE
ARE SEEING IN THESE GENES.
CAN YOU READ THIS WRITING IN THE
RED BOX?
BECAUSE I CAN'T.
I HAVE BAD EYES ANY WAY.
SO, THE MODEL WE HAVE IS THAT
YOU CAN TURN ON THE INNATE
IMMUNE RESPONSE EITHER WITH AN
INSULT LIKE STROKE OR VASCULAR
EVENT, TRAUMATIC BRAIN INJURY OR
NEUROTOXIN, MAYBE INFECTION, THE
IMMUNE SYSTEM STARTING TO GO
DOWN AND BLOOD BRAIN BARRIER IS
NOT HOLDING UP AS WELL.
THIS TURNS IT ON.
ALSO TURN ON THE INNATE IMMUNE
RESPONSE WITH A BETA.
IT'S AN INSULT TO THE BRAIN.
EITHER WAY.
NOW, WHEN THE INNATE IMMUNE
RESPONSE TRIGGERED, THESE GENES,
NOT SOME OF THESE CONTROL INNATE
IMMUNE RESPONSE YOU'LL HAVE,
SOME CONTROL HOW ROBUST
INFLAMMATION WILL BE.
SO WE ARE SEEING THIS GROWING
TREND TOWARDS GENES SHOWING UP
IN GWAS AND ALZGENE THAT CONTROL
INNATE IMMUNE RESPONSE.
SO THE MODEL THAT COMES OUT OF
THIS, AS WE AGE, THERE ARE
INSULTS TO THE BRAIN.
SOME INVOLVING GENETICS LIKE
VASCULAR GENES SHOWING UP THAT
MIGHT INCREASE YOUR RISK FOR
NEUROVASCULAR EVENTS.
NOTICE OR UNNOTICE STROKE OR
MINISTROKE.
HOW YOUR BRAIN RESPONSED TO
INSULTS IS REGULATED BY VARIOUS
GENES THAT ARE SHOWING UP IN
THESE STUDIES IF YOU
OVERRESPOND, IF HAVE YOU TWO
ROW -- TOO ROBUST RESPONSE TO
INSULTS, YOU MAY MAKE TOO MUCH A
BETA AS PART OF THE INNATE
IMMUNE RESPONSE WHERE THESE
GENES ARE INVOLVED WITH THE
PRODUCTION OF A BETA.
WE KNOW THAT FOLLOWING STROKE,
BASE LEVELS GO UP.
WE PUBLISHED A PAPER ON THIS
SHOWING A MECHANISM FOR HOW BASE
GOES UP.
BOB HAS ALSO SHOWN THIS.
THE WAY A BETA GOES UP IS FIRST
BASE LEVELS GO UP, AND BASE IS
THE RATE LIMITING STEP.
WE HAVE GENES THAT EFFECT
AGGREGATIONS SHOWN HERE.
AND THIS WILL AFFECT HOW MUCH A
BETA ACCUMULATES IN THE BRAIN,
LEADING TO PLAQUES AND SYNAPTIC
DYSFUNCTION AND NOW YOU HAVE NEW
INSULT AND RESPONSE GETS TURNED
ON AGAIN AND A VICIOUS CYCLE.
THIS IS THE NEW MODEL WOO WE
HAVE FOR DISEASE IN LINE WITH
OTHERS WHO ARE SUGGESTING THIS
DISEASE STARTS WITH INSULTS BUT
YOUR REACTION TO THAT INSULT
MODULATED BY GENETICS THAT MIGHT
DETERMINE WHEN YOU GET THIS
DISEASE OVER YOUR LIFETIME.
SO THIS IS SOMETHING THAT WE ARE
EXPLORING.
NOW WHAT SHOULD THE INNATE
RESPONSE BE IN ALZHEIMER'S IN
COULD BE INFECTION.
THESE ARE SOME OF THE INFECTIONS
INDICATED.
IT COULD BE A TRANSGENT
INFECTION.
IT COULD BE INFLAMMATORY
RESPONSE.
YOU COULD HAVE A NONINFECTIOUS
INSULT TRIGGER.
WE SHOWED THAT CERTAIN INHALANT
ANESTHETICS DRIVE UP BASE LEVELS
AND A BETA LEVELS.
ANESTHESIOLOGISTS ARE UPSET WITH
THAT.
BRAIN TRAUMA BRAIN INJURY WILL
DO THIS.
AND AS I MENTIONED, WE BELIEVE
THE REASON WHY A BETA GOES UP IN
THE INNATE IMMUNES IS IS IT'S A
POTENT MICROPEPTIDE.
WE PUBLISHED THIS LAST YEAR.
A BAIT AT 42 EXHIBITS
ANTIMICROBIAL ACTIVITY AGAINST
EIGHT DIFFERENT ORGANISMS AND A
BETA 42 HAS MORE ANTIMICROBIAL
ACTIVITY NE40 AND THESE ARE SOME
OF THE -- IN SOME CASES A BAIT
AT 42 IS MORE POTENT THAN THE
CLASSIC ANTIMICROBIAL PEPTIDE.
A BETA 42 BY VARIOUS
MICROBIOLOGICAL ASSAYS IS NOW
THE MOST POTENT PEPTIDE FOR
HITTING CANNED DANTAL BICANS AND
EPIDERMIS AND MONOCYTEO GENES.
SO NOW LOTS MORE WORK NEEDS TO
BE DONE TO SEE THE EFFECTS OF
THIS IN-VIVO.
WE JUST SHOWED THE MICROBIOLOGY
DATA THAT DOES LOOK FOR ALL
INTENSE PURPOSES TO ACT LIKE A
PEPTIDE.
ALSO HAS A BETA 42 CAN WORK AS A
MICROBIAL PEPTIDE BECAUSE IT CAN
MONTH LIGMERRIZE AND WE ALSO
SHOW IF YOU LOSE CONTROL OF A
BETA, SCRAMBLED A BETA, IS IT
HAS NO EFFECT.
I WANT TO SHOW A QUOTE FROM
LEONARDO DIVISNY.
 DIVINCI.
I WOULD ADD THAT A BAYA IS IN
THIS CATEGORY.
WE ALWAYS THOUGHT IT IS JUMP,
JUST MADE IN THE -- JUNK, CRAP
MADE IN THE BRAIN.
NOW IT'S LOOKING LIKE AN
ANTIMICROBIAL PEPTIDE.
SO IT COULD HAVE SOME AFFECT
BASICALLY IN HELPING THE BRAIN'S
INNATE IMMUNE SYSTEM EVEN IF
IT'S TURNS ON ACCIDENTLY, AND
MORE RECENTLY, WE WORKED
ON -- WHEN HE IT WAS ADDRESSED
HOW THE A BETA MONTH LIGMERS AND
PURE DATA POTENTIATION -- MOW
LIGMERS.
IT WAS SUGGESTED THAT A BETA IS
BEING MADE AS A NATURAL NEGATIVE
FEEDBACK ON LTP.
THAT IT IS A NATURAL WAY
SYNAPSE.
ALSO RELEASING OTHER AGENTS AND
SYNAPSES THAT THE POINT AND
INDUCING LONG TERM DEPRESSION.
SO YOU DON'T WANT THIS LONG TERM
POTENTIATION.
YOU NEED LONG TERM POTENTIATION
AND THEN CHECK AND BALANCE.
HE IS SUGGESTING A BETA MAY BE
PART OF THAT.
I WANTED TO CLOSE AND PROPOSE
THAT A BETA MAY BE UP REGULATED
IN RESPONSE TO INJURY TO DO TWO
THINGS.
ONE, AS A NEUROMODULATOR,
CROWNING NEURAL ACTIVITY BY
BRINGING DOWN LTP AND TURNING
OFF THE DAMAGED PART OF THE
GRID, TWO BY PROTECTING
ANTIMICROBIAL PEPTIDE AGAINST
THE INFILTRATION AGAINST BLOOD
BORN PATHOGENS WHERE YOU MAY
HAVE A BLOOD BORN BARRIER, DIKE
TRAUMATIC BRAIN INJURIES.
THIS ISN'T UNUSUAL FOR THE
INNATE IMMUNE SYSTEM.
WE BEEN CYTOKINES THAT HAVE BOTH
ANTIVIRAL ACTIVITIES AND A
NEUROMOD ORATORY.
-- NEUROMODULATORY.
IN THIS CASE, AS I GET INTO THE
LAST PART OF THE TALK ABOUT
THERAPY, WE NEED TO REMEMBER
THAT ANTIA BETA DRUGS SHOULD
PROBABLY DIAL DOWN THESE LEVELS
IN THE BRAIN TO A SAFE LEVEL BUT
DON'T WIPE THEM OUT.
IS THERE TO THE WAY WE USE
STATENS TO DIAL DOWN CHOLESTEROL
LEVELS.
YOU DON'T WANT IT ALL THE WAY
OUT.
YOU NEED CHOLESTEROL.
HOW DO WE GET THE STATENS OF
ALZHEIMER TO BRING DOWN
INCIDENTS IN THE SAME WAY VE
HAVE BEEN SUCCESSFUL WITH HEART
DISEASE?
THE FIRST ATTEMPTS VIOLENT BEEN
VERY GOOD.
FIRST GENERATION DRUGS LARGELY
FAILED.
EITHER THEY WEREN'T SAFE, THEY
DIDN'T GET INTO THE BRAIN, THEY
WEREN'T POTENT OR ALL OF THE
ABOVE.
FOR EXAMPLE, THERE WAS A GAMMA
SERETASE INHIBITOR THAT FAILED
BECAUSE YOU NEED GAMMA SERETASE.
YOU CAN'T JUST INHIBIT IT.
IT CAUSES ALL KINDS OF SIDE
EFFECTS BY HITTING IT WITH A
SLEDGE HAMMER.
SO I'LL TELL YOU ANOTHER
APPROACH.
THE FIRST GAMMA SERETASE
MODULATOR SELECTIVELY BLOCKS
GAMMA SERETASE ON APP TO ALLOW
OTHERS TO MOVE.
RIGHT IDEA BUT IT FAILED BECAUSE
OF POSTENCEY AND BRAIN
AVAILABILITY.
IT BLOCKS OUT AGGREGATION AND IT
WASN'T VERY BOATENT AND DIDN'T
GET INTO THE BRAIN VERY WELL AND
FAILED.
WE ARE STILL WAITING FOR
AGGREGATION DRUGS.
THE FIRST IMMUNOTHERAPY
APPROACH, ACTIVE VACCINATION,
FAILED BECAUSE OF SAFETY ISSUES.
THERE WAS A T-CELL PROBLEM.
NEW ATTEMPTS ARE NOW BEING MADE
TO GET AROUND THAT.
THE IDEA OF MAKING ANTIBODIES TO
A BETA BY VACCINATION IN THE
ANTIBODIES THEN CLEARING A BETA
FROM THE BRAIN BY DRIVING GLIAL
DEGRADATION OF A BETA.
IT WORKS AND IT'S GOING ON HERE
BUT THE FIRST ONE FAILED BECAUSE
OF SAFETY.
THEN THERE WAS THE DRUG FROM
RUSSIA, THE ANTIHISTAMINE THAT
WAS GOING TO CURE ALZHEIMER'S
DISEASE.
AFTER A TRIAL, IT BECAME THE
BOMB AND IT WENT AWAY.
BUT WE HAD HIGH HOPES FOR IT.
THIS IS SUCH A TERRIBLE DISEASE.
HOW YOU YOU HOPE ANY OF THESE
THINGS WILL WORK.
PATHWAYS OF SECOND GENERATION
DRUGS.
I WANT TO TELL YOU ABOUT GAMMA
SERETASE MODULATORS.
OTHER COMPANIES LIKE BRISTOL
MIRE SQUIBB ARE DEVELOPING NOTCH
SPARING GAMMA SERETASE
INHIBITORS ALLOWING NOTCH TO BE
CLEAVED.
BETA SERETASE INHIBITORS ARE IN
THE WORKS AS WELL.
NOW BAP NEWS MAP, THIS IS
PASSIVE IMMUNOTHERAPY INJECTING
ANTIBODIES TO A BETA.
THESE PRESUMABLY GET INTO THE
BRAIN AND TRIGGER A BETA
DEGRADATION.
LOTS OF NEW ATTEMPTS GOING ON
AND I WANT TO TALK ABOUT TWO OF
THEM.
FIRST I WANT TO TALK ABOUT GAMMA
SERETASE MODULATORS.
AND THIS IS A PAPER THAT STEVE
WAGNER, MY CLOSE COLLEAGUE AND
FRIEND AND I AND OTHERS
PUBLISHED IN NEURON THIS PAST
SUMMER.
FIRST, GAMMA SERETASE POD LATER
HITS THE GAMMA SERETASE COMPLEX
HAD A VERY STRONG EFFECT IN
MOUSE MODELS OF ALZHEIMER'S
DISEASE.
WHAT THESE GAMMA SERETASE
MODULATORS DO IS THEY BASICALLY
TAKE ADVANTAGE OF THE FACT THAT
WHAT DO WE KNOW ABOUT THESE
MUTATIONS IN THESE MUTATIONS AND
APP ARE MOSTLY INCREASING THE
RATIO OF 42-40.
ONE DAY STEVE WAGNER AND I WERE
PLAYING TENNIS IN THE 90's AND
HE SAID, WHAT IF WE START A
COMPANY AND TRY TO FIND DRUGS
THAT INCREASE THE RATIO OF
40-42?
JUST REVERSE IT.
FIX IT BY REVERSING THE RATIO
THE OTHER WAY?
AND THEN THIS IS HOW WE CAME UP
WITH THE NAME GAMMA SERETASE
MODULATOR.
SO, WE STARTED THIS COMPANY
CALLED NEUROGENETICS IN 99,
SCREENED FOR COMPOUNDS HOW TO DO
THIS.
AND WE FOUND THEM.
WHAT THEY DID IS THEY BASICALLY
DRIVE 42 DOWN, THEY LEAVE 40
ALONE, THEY DRIVE UP 38 AND 37,
WHICH ARE NONAMYLOIDGENIC.
THEY DON'T AGGREGATE.
SO YOU GOT NO CHANGE IN A BETA
LEVELS BUT THE RATIO OF 42-40
WAS NOW DECREASED, THE OPPOSITE
OF THE MUTATIONS.
AND UNLIKE GAMMA SERETASE
INHIBITORS, THEY DON'T INTERFERE
WITH GAMMA SERETASEFULLY, WHICH
IS THE SUBSTRATE LIKE
NOTCH -- AND SO YOU ALSO
DETERMINED THE MOST LIKELY
TARGET STILL TO BE CONFIRMED ARE
THE COMPLEXES 10 I THE SERETASE
COMPLEX ARE THE THE ONES WE SPOKE OF
EARLIER.
SO THIS IS JUST SHOWING THE MASS
SPECK DRIVING UP THERE TO 738,
THIS IS ALL PUBLISHED IN THE
PAPER.
WE ARE DOING NOTHING TO NOTCH AT
ALL, EVEN AT HIGH DOSES NOT
EFFECTING NOTCH CLEAVAGE WHILE
OTHER SUBSTRATES ARE MAKING IT
FATE.
WE WIPED OUT BLACKPRETTY GOOD.
THESE ARE MICE THAT WERE SACK
FIGHTING AT 15 MONTHS, TREATED
FOR SEVEN MONTHS WITH THE DRUG.
PLAQUE IS BEING WIPED OUT PRETTY
WELL.
AND THEN THIS IS THE DRUG.
THESE DRUGS ARE DIAERIAL AMINO
THIGHA SOLS.
HERE IS THE PROBLEM.
SO WE PUBLISHED THESE DRUGS BUT
THE ONES WE PUBLISHED DON'T HAVE
VERY GOOD VIABILITY AND SOME OF
YOU KNOW IN DRUG DEVELOPMENT,
THE DRUG ISN'T VERY SOLUABLE IN
WATER.
IT CAN BE CEMENT IN THE BODY.
IT'S TOUGH TO GET IT OUT.
SO, A DRUG WITH LOW SOLUBILITY
LIKE THESE ORIGINAL ONES WHERE
THE SOLUBILITY WAS LOW
NANOMOLAR, THEY GET INTO THE
BRAIN REAL, REALLY WELL BUT THEY
ARE TOUGH TO GET BACK OUT.
SO THEY WERE NOT THE BEST
CANDIDATES FOR DRUG DISCOVERY.
WHAT STEVE AND I DID, HE IS NOW
AT UCSD, WE DESIGNED 40 NOVEL
GXM DESIGNED TO BE MORE
SOLUABLE.
AND WE WERE SUCCESSFUL.
WE NOW HAVE GSMs IN THE SAME
CLASS TO WORKED THAT NOW HAVE 10
MICROMOLAR SOLUBILITY.
DRUG COMPANIES THEN SAY THAT'S
GREAT.
THAT WILL CLEAR.
SO THESE ARE IN CLINICAL
DEVELOPMENT AT MGH AND UCSD AND
WE ARE DOING BASICALLY
EVERYTHING WE NEED TO DO, ANIMAL
STUDIES, LOOKING AT TOX AND
PHARMACOKINETICS AND DYNAMICS
AND HOPING THESE WOULD BE A MORE
SUPER BETTER VERSION OF THESE
ORIGINAL AREAS OF.
THESE.
I SHOULD SAY THAT STEVE AND I
ARE VERY HAPPY ABOUT THE FACT
THAT MANY PHARMACEUTICAL
COMPANIES BASICALLY WORKING
AROUND THE PATENTS OF THESE
DRUGS TO MAKE NEW VERSIONS.
AND I THINK IF YOU'RE A BIOTECH
COMPANY YOU GET UPSET BECAUSE
YOU DON'T WANT TO BE PATENTED.
WE ARE ECSTATIC BECAUSE WE HOPE
ANY PHARMACEUTICAL COMPANY WHO
WORKS AROUND THIS CLASS OF DRUG
WILL COME UP WITH SOMETHING THAT
IS GOING TO BE TREATING THE
DISEASE, PREVENTING A BETA
PRODUCTION SAFETILY.
SO IT'S NOT JUST US DOING THIS.
THE PHARMACEUTICAL COMPANIES
AROUND THE WORLD WORKING WITH
THIS AND IT'S MY HOPE THESE WILL
BECOME THE MODULATORS THAT MIGHT
BE THE STATENS OF ALZHEIMER'S.
BEFORE I END, I WANT TO TALK
ABOUT ONE MORE DRUG AND THAT IS:
THIS IS A DRUG THAT BINDS ZINC
AND IN MANY CASES ALSO PROPER.
IT DOESN'T HOLD IT.
IT ACTUALLY WILL DELIVER THAT
METAL TO THE CELL, BE
INTERNALIZED AND REDISTRIBUTE
THAT MESTAL TO OTHER PROTEINS
WITH A HIGHER AFFINITY FOR THE
METAL THAN THE DRUG.
SO IT'S NOT A CURE LATER.
THE ONE I WANT TO TALK ABOUT IS
PBT2.
SO FIRST LET ME TELL YOU THE
ORIGINAL METAL HYPOTHESES THAT
BUSH AND I DEVELOPED WHEN HE WAS
MY POSTDOC.
HE IS NOW BACK IN AUSTRALIA.
WHAT WE FOUND IN THE 90s ZINC
AND COPPER PROMOTE AGGREGATION
OF A BETA.
AND WE SHOWED FROM FIRST IN THE
TEST TUBE AND THEN TO TRANSGENIC
ANIMALS AND AGGREGATES COLLECT
OVER DECADES.
AND THESE EXCESSIVE AGGREGATES
SEQUESTER ZINC AND COPPER.
ZINC AND COPPER ARE NEEDED FOR A
LOT OF THINGS INCLUDING MENTAL
HEALTH AND LTP.
SO, THINK ABOUT A DRAIN FULL OF
AMYLOID THAT A NEURAL
PATHOLOGYGIST AND C.
AND IF YOU TAKE ZINC 7
RADIOACTIVE COP OR OR DO A METAL
NAPPING OF THE BRAIN, YOU WILL
SEE AMYLOID IS COVER WITH ZINC
AND COPPER.
IT'S SUCKING IT UP WITH 10 TO
THE MINUS 12.
IT'S NO ACCIDENT.
THE ONE THING WE KNOW ABOUT A
BETA.
WE DON'T KNOW HOW IT IS TOXIC IN
THE BRAIN.
WE KNOW LIGMERS EFFECT LTP AND
COMPARE LTP AT HIGH DOSES, BUT
THE MECHANISM IS UNKNOWN.
BUT ONE THING WE KNOW IS A BETA
IS A GOOD METAL BINDING PEPTIDE.
10 TO THE MINUS 12KB.
I BELIEVE THAT ZINC BY A BETA
WILL BE 5 NEURON SYNAPSES WITH
ZINC AND THIS WE CALL THE
AMYLOID TRAP HYPOTHESES.
MEANWHILE, COPPER BOUND BY AG
GATES ARE SHOWN TO GENERATE
REACTIVE OXYGEN SPECIES.
SO DOUBLE WHAMMY.
THEY ARE DEPRIVING THE CELL OF
ZINC AND COPPER AND REACTOR
METAL COPPER GOING DOWN TO
CHEMISTRY WILL GENERATE FREE
RADICALS.
NOT A GOOD THING TO HAVE AMYLOID
SITTING AROUND WITH METAL IN THE
BRAIN.
THAT'S DEMONSTRATED HERE IN THIS
DIAGRAM.
SO THE AMYLOID TRAP HYPOTHESES
SAYS, AS YOU DO THIS, YOU HAD A
ZINC DEFICIENCY AROUND NEURONS
AND YOU GET COPPER INDUCED
REACTIVE OXYGEN SPECIES AND I
WON'T GO INTO THIS MUCH BUT WE
ARE TESTING THE HYPOTHESES THAT
PERHAPS THIS WILL BE THE ZINC
DEFICIENCY WILL NEED TO BE
DESTABILIZATION OF MICROTUBULES
BECAUSE THEY SUCK UP MOST OF THE
ZINC IN THE CELL.
THEY ARE COORDINATED BY ZINC.
SO WON'T FIRST THING YOU THINK
ABOUT IF YOU HAVE A ZINC
DEFICIENCY, BECAUSE THE AMYLOID
SEQUESTERING IT, MICROTUBULES
THEMSELVES.
NOW THE FIELD OF ALZHEIMER'S
DISEASE BELIEVES THIS, TO YOU
BECOMES HYPERPHOSPHORYLATIONS
AND FALSE OFF AND THEN IT
BECOMES DESTABILIZED AND NOWY
GET A TRANSPORT PROBLEM.
BECAUSE IT'S NOT INTO AGGREGATE
OUTSIDE OF THE MICROTUBULES.
WHAT IF IT'S THE NOPS WHAT IF WE
GOT IT BACKWARDS?
WHAT IF FIRST MICROTUBULES
BECOME STABILIZED.
THIS THE IS JUST SPECULATION
HYPOTHESES BUT TESTING IT IN A
NUMBER OF DIFFERENT FOLKS AROUND
THE WORLD.
WHAT IF BY HAVING NOT ENOUGH
ZINC TO COORDINATE THE
MICROTUBULE CYLINDER THAT
MICROTUBULES BECOME UNSTABLE
FIRST?
FIRST DESTABILIZATION AND THEN
TO YOU FALLS OFF AND THEN AG
GATES -- TO YOU.
BECAUSE ITS PLATES ARE EXSPORTS
AND -- EXPOSED.
THIS IS A HYPOTHESES WE ARE
PUTTING FORWARD AS AN EXTENSION
OF THE TRAP HYPOTHESES TO HOW
MIGHT GO FROM AMYLOID TO -- WE
JUST DON'T KNOW YET HOW YOU GO
FROM AMYLOID TO TANGLES AND WE
NEED TO KNOW HOW THAT HAPPENS.
EARLY DAYS, WE ARE STILL
STARTING TO DO THIS BUT I
THOUGHT IT WOULD BE INTERESTING
TO SHOW YOU THIS HYPOTHESES.
ALMOST SHAMELESS SPECULATION.
BORDERING ON SHAMETH
SPECULATION.
WE HAVE A DRUG CALLED PBT2.
IT WAS STARTED IN MY LAB WITH 97
WITH ANGEL FUNDING AND NOW IT'S
PUBLIC IN AUSTRALIA AND OFF ON
ITS OWN ALTHOUGH I STILL CONSULT
FOR THEM.
BUT THIS DRUG IS A ZINC COPPER
ION I FLORA.
IT PREVENTS INTERACTION OF A
BETA RESISTANT COPPER BECAUSE
IT'S A LITTLE STRONGER THAN A
BETA.
COPPER HAS 10 TO THE MINUS 14
AFFINITY FOR COPPER AND ZINC.
SO IF YOU HAVE THE A BETA
AGGREGATES, SEQUESTER HAVE GONE
ZINC AND COPPER, IT WILL STRIP
THE METAL AWAY FROM AMYLOID AND
TAKE IT AWAY AND AT THAT POINT
IF THE A BETA HAS NOT BEEN
COVARIANTLY CROSSLINKED AND ALL
THIS STUFF IS PUBLISHED, THAT
I'M SAYING IN VARIOUS PAPERS, A
LOT OF THE A BETA WILL BE
DISSOLVED BACK DOWN TO MONOMERS
BECAUSE THE NONCROSSING A BETA
IS HELD TOGETHER WITH ZINC AND
COPPER AS A SALT.
METAL SALT.
WE ARE DOING THIS AS WELL OVER
THE YEARS AND IT'S INTERESTING.
SO NOW THIS STRIPS COPPER AND
MUCH OF THE A BETA IS DISSOLVED
AND MOST IMPORTANTLY TO ME, I
THINK, IS THAT THESE THEN
REDISTRIBUTE THESE METALS BACK
TO THE CELL WHERE THEY HAVE THIS
COFACTOR FOR SAB1, SOME COMBINE
ET CETERA SO YOU RESTORE WHAT
MIGHT BE A DEFISH OF
ZINC -- DEFICIENCY AS IT GOES UP
IN THE BRAIN.
SO, IT ALSO PREVENTS FREE
RADICAL PRODUCTION BECAUSE IT
DOES THE SAME THING FOR COPPER.
THE COPSIER FOUND AND THE A BETA
WILL GENERATE FREE RADICALS AND
TAKE THE COPPER AND REDISTRICT
THAT.
SO THIS IS THE DRUG.
I WANT TO SHOW YOU WE PUBLISHED,
THIS DRUG HAD AMAZING NUTS
TRANSGENIC MICES AND A NEW PAPER
CAME OUT YESTERDAY SHOWING IT
PROTECTS SYNAPSES AND HAS A
PROTECTION EFFECT IN THESE MICE
AS WELL.
THIS PAPER JUST CAME OUT I THINK
ON TUESDAY.
THIS IS THE ORIGINAL PAPER
SHOWING THAT EVERYTHING YOU WANT
A DRUG TO DO IN AB MICE, IT DID.
IT RESTORED COGNITION, IT
PREVENTED THE EFFECTS ON LONG
TERM POTENTIATION, IT REDUCED
BETA AND BLACKS ET CETERA.
MORE IMPORTANTLY, IN A CLINICAL
TRIAL, A SMALL ONE.
A PHASE 2A, 12 WEEKS, 78
PATIENTS, SMALL.
WHERE THE PRIMARY OUTCOME IS TO
AFFECT THE SAFETY AND
TOLERABILITY, THE SECONDARY
OUTCOMES ARE AFFECTS ON
COGNITION.
AND THIS DRUG BASICALLY ON THE
SMALL TRIAL SIGNIFICANTLY
IMPROVED COGNITION.
IT SIGNIFICANTLY IMPROVED
EXECUTIVE FUNCTION ON THE
NEUROPSYCHOLOGICAL TEST BAST
REAND THE COG WASN'T QUITE
SIGNIFICANT.
AND THIS IS JUST 12 WEEKS, 78
PATIENTS.
WHEN PRESENT THESE DATA TO A
PHARMACEUTICAL COMPANY THAT SOME
MIGHT SAY, WOW, WE HAVE THESE
EFFECTS IN JUST 12 WEEKS.
78 PATIENTS.
AND A LOT OF THE OTHERS WERE
SAYING, BUT IT'S ONLY 12 WEEKS,
78 PATIENTS.
SO IT JUST SAYS THIS IS JUST AN
EARLY NICELY DONE, BUT YOU NEED
TO DO THE PHASE II AND PHASE
III, 500 PATIENTS FOR ONE YEAR
AND IF THE COMPANY IS NOW
PLANNING TO DO THAT, ENTERING
THE STAGES GETTING THAT GOING.
SO, THIS DRUG BASICALLY A
MECHANISM SEEMS TO BE WORKING
THROUGH THIS TRAP HYPOTHESES.
IT'S STRIPPING THE ZINC AND
COPPER AWAY CAUSE THE SOLUTION
OF A BETA AND AGAIN ALL OF THIS
PUBLISHED.
I WANT TO MENTION THAT IN
ANOTHER PAPER, THEY MADE A ZINC
T THREE KNOCKOUT.
ZNT3 IS A ZINC TRAPS POUREDDER
THAT RELEASES ZINC INTO THE
SINCALS -- TRANSPORTER.
WHEN THEY KNOCKED IT OUT SO YOU
COULDN'T GET ZINC RELEASED INTO
THE SYNAPSE, THEY BECAME
DEMENTED BY 6 MONTHS OLD.
IN THE AGED BRAIN, IT GOES DOWN
WITH AGING.
THE MODEL HERE IS THAT IF YOU
HAVE A WHOLE LOT OF EXPRESS
LIGMER, MORE THAN YOU WOULD NEED
ACCORDING TO THE HYPOTHESES JUST
IN THE NATURAL CHECK AND
BALANCE, IF YOU HAVE TOXIC
FUNCTION, EXPRESS LIGMERIN THE
SYNAPSE, IT WILL BIND TO ZINC
AND BE A PHENOCOPIY AND MIMIC OF
NOT HAVING ZINC PRODUCED AT ALL.
SO THAT'S HOW THEY THINK THE
ZNTP KNOCKOUT WHICH REDUCES ZINC
RELEASE HAS THE SAME MECHANISM
TO IMPAIRING LTP AS IF HAVING
MORE MONTH LIGMERBINDING.
AND THIS IS A PAPER THAT CAME
OUT LAST YEAR.
SO, IF I HAD TO GUESS RIGHT NOW
BASED ON WHAT WE ARE DOING OR
WHAT WOULD BE A NICE DRUG FOR
AD, A STATEN, I WOULD THINK
GAMMA SERETASE MODULATOR BECAUSE
OF THE BETA LINE.
IF YOU HAD CONGESTIVE HEART
FAILURE, YOU WOULDN'T TREAT WITH
A STATEN.
YOU HAVE TO FIX THE HEART.
I THINK THE MODULATORS ARE MOST
USEFUL, PREVENTIVELY TO USE THEM
TO JUST STYLE YOUR BETA LEVELS
DOWN TO A SAFE AMOUNT.
I THINK THE MORE ACUTE
TREATMENT, IF YOU BELIEVE THAT
THE PROBLEM IS FREE RADICAL
PRODUCTION BY BINDING COPPER IF
WE BELIEVE THAT THE A BETA IS
TRAPPING THESE METALS AND
DEPRIVING NEURONSES SATURDAY
ZINC, WHICH ARE ALSO IN
DEVELOPMENT.
THIS IS TWO EXAMPLES OF THE
DRUGS IN THE SECOND WAVE, THE
SECOND PIPELINE FOLLOWING THE
FAILURES.
THERE ARE OTHER THINGS.
ALL KINDS OF OTHER THINGS.
WE ARE BRINGING NEW TAU DRUGS AS
WELL.
THIS IS JUST TWO EXAMPLES.
MY HOPE IS WE WILL HAVE A DRUG
THAT WILL TREAT AND PREVENT THIS
DISEASE OVER THE NEXT DECADE.
SO I WANT TO END WITH THIS
SLIDE.
AVERAGE LIFE SPANS FROM 1800 TO
1900, 35 YEARS TO 50 YEARS.
WHY?
BECAUSE OF THE -- 1900-2000,
50-75.
AGAIN MAINLY ANTIBIOTICS, MODERN
MEDICINE.
WHAT WHAT IS GOING TO HAPPEN
THIS SENT RE?
PHARMACOGENETICS.
ONE AVERAGE LIFE MAN IS THIS
CENTURY IS 175 -- 75 YEARS TO
110 YEARS.
WHAT WILL DO IT?
LEARNING OUR GENOME, USING GENES
TO PREDICT EARLY, PREVENT EARLY,
AND ERADICATE DISEASE BEFORE IT
EVEN BEGINS IN AGED INDIVIDUALS.
IT'S MY HOPE THIS IS HOW WE ARE
GOING TO ACHIEVE OUR AGE-RELATED
DISEASES.
EARLY DETECTION AND PREVENTION.
I WANT TO THANK ALL THE MEMBERS
OF MY LAB TO MAKE THIS POSSIBLE.
ALL MY COLLABORATORS.
ESPECIALLY THE CURE ALZHEIMER'S
FUND, NIH, NIMH AND THE FUNDING
AND THANK YOU ALL FOR YOUR
ATTENTION.
THANK YOU.
[APPLAUSE]
>> TERRIFIC.
WE HAVE TIME FOR SOME QUESTIONS.
ALTHOUGH IT'S RUNNING A LITTLE
LATE BUT THERE ARE MICROPHONES
IN THE AISLES FOR THOSE WHO
WOULD LIKE TO POSE A QUESTION
AND LET ME START.
YOU MADE A INTERESTING CASE FOR
THE ROLE OF INNATE IMMUNITY AS
PLAYING A ROLE IN THIS DISEASE
AND FOR A BETA AS A MAJOR PLAYER
WHEN I THOUGHT WHEN YOU GOT TO
THE THERAPEUTICS THERE WAS GOING
TO BE SOMETHING IN THAT PATHWAY
AS WELL AS A WAY TO TRY TO
INTERVENE.
SO WHAT IS THAT CONNECTION?
WHAT CAN YOU USE WITH OR DO WITH
THAT HYPOTHESES THAT MIGHT BE
THERAPEUTICALLY INTERESTING?
>> WELL, I THOUGHT I ENGAGED IN
ENOUGH SHAMELESS SPECULATION.
>> NO, GO AHEAD.
>> IF I HAD TO, I THINK THAT
CD33 IS A GREAT TARGET BECAUSE
WHAT IT ISDa÷
THE GENETICS IS WORKING IS THAT
IN RESPONSE TOe$Kp
mb INSULT AND OVERLY
ROBUST ACTIVATION OF THE INNATE
IMMUNE RESPONSE IS WHAT IS
LEADING TO PROBLEMS.
TOO MUCH A BETA AND TOO MUCH
INFLAMMATION.
YOU WANT TO, IN THOSE WHO ARE
OVERREACTING TO INSULT AND HAVE
TOO MUCH INNATE IMMUNE RESPONSE,
YOU WANT TO DIAL IT DOWN.
CD33 IS THE GATEKEEPER.
SO CD33, WHEN BOUND TO LIGAND,
AND WE KNOW THERE ARE TROOPS
THAT WILL ACTUALLY TONE DOWN THE
INNATE IMMUNE RESPONSE.
SO IF YOU HAD A DRUG THAT HIT
CD33, SAFELY, AND REGULATING
INNATE IMMUNE SYSTEM, THAT WOULD
BE MY GUESS.
>> IS THERE A MOUSE EXPERIMENT?
>> YES.
THERE IS CD33 TRANSGENICS AND
KNOCKOUTS.
WE ARE BEGINNING TO GO IN THAT
DIRECTION ALREADY.
WE HAVE BEEN THINKING A LOT
ABOUT IT FOR 2-3 YEARS.
>> ARE WE GOING BACK TO THERAPY
OF THE BRAIN?
>> NO.
>> WE HAVE -- DISEASE USING
THERAPY --
>> NO.
THAT'S NOT THE ANSWER HERE.
THE PROBLEM IS THE METALS ARE
ALREADY BOUND.
SO KEY LAY WILL MAKE THINGS
WORTS.
>> BUT HOW YOU GOING TO GET IT
INSIDE TO TRAP IT BECAUSE --
>> THAT'S WHAT I PRESENTED.
ZINC ION FORES WILL BIND THE
METALS BUT THEN TAKE THEM TO THE
CELL.
YOU HAVE TO HAVE -- KEY LAY HAS
A KD OF 10 TO THE MINUS 20 OR
28T WILL BIND METALS AND NOT LET
THEM GO.
THAT MIGHT DISSOLVE THE AMYLOID
BECAUSE THAT WON'T SOLVE THE
PROBLEM.
YOU NEED TO MAKE THOSE METALS
AVAILABLE AGAIN.
THAT'S WHAT IT DOES.
>> SO HOW YOU GOING TO DELIVER
IT?
ATERMINUSLY?
>> NO.
SMALL MOLECULES.
THE CLINICAL TRIAL I SHOWED,
MOLECULES ARE AVAILABLE AND GETS
INTO THE BRAIN WITH GOOD
VIABILITY AND BINDS TO METALS
AND REDISTRIBUTES THEM.
SO NO CHELATION FOR SURE.
>> SO IT'S MY UNDERSTANDING THAT
A LOT OF THE GWAS IDENTIFIED
SNPS HAVE TURNED OUT TO BE
RELATED TO -- NOT IN THE CODING
REGION AND THEY PRESUMABLY ACT
BY REGULATING THE AMOUNT OF GENE
PRODUCT.
AND I'M JUST WONDERING WHETHER
YOU THINK THAT IF ONE LOOKS AT
THE RARE SUB SET OF THOSE THAT
ACTUALLY ARE IN THE GENE, YOU
WILL FIND SOMETHING SIMILAR TO
WHAT YOU FIND, THAT THESE ARE
RARE MUTATIONS THAT ARE MORE
RECENT AND OTHER SNPS ARE JUST
THE HAPPEN LAP MARKER.
I DISAGREE.
I 
SNPS ON THE CHIP ARE JUST OLD
VARIETIES THAT ARE VERY COMMON
BUT MOSTLY HAVE NO EFFECT
BIOLOGICALLY AND ARE JUST ON
LINKAGE EQUILIBRIUM WITH
POSITIVE VARIANTS EITHER COMMON
OR -- I BELIEVE A LOT OF RARE
ONES HAVE YET TO BE FOUND SO YOU
HAVE TO FOLLOW-UP THOSE SNPS AND
THAT WAS THE BELIEF.
A LOT AFFECT SPLICING BUT I
HAVEN'T SEEN THE DATA.
I HAVEN'T SEEN REALLY MUCH COME
OUT OF ON THAT SO I THINK FOR
US, GIVEN OUR EXPERIENCE, THESE
COMMON
8
WHERE TO FIND VARIANTS DUE TO
BIOLOGY AND SHOW IT.
AND I THINK WE WILL SEE A COMMON
DISEASE WITH LOTS OF RARE
VARIANTS RATHER THAN COMMON
DISEASE AND COMMON VARIANTS.
>> LET ME PUSH YOU AROUND A
LITTLE BIT.
THIS IS A BIG DEBATE IN THE
GENETICS COMMUNITY.
SO IF YOU TAKE OUT YOUR 7
FAMILIES WHERE YOU HAVE A RARE
VARIANT THAT APPEARS TO BE
FAIRLY HIGHLY PENETRANT, DOES
THE ADAM 10 GO AWAY?
>> YES.
BECAUSE THOSE FAMILIES ARE
PRETTY GOOD SIZE AND THE
FAMILY-BASED WAS THAT WAS ENOUGH
TO DRIVE THE INITIAL P VALUES TO
.01.
SO IT WAS EASY TO GET RID OF
THIS.
>> SO THEREBY WILL BE CASES AND
MAYBE THE LDL RECEPTOR IS A GOOD
EXAMPLE THAT CAUSE HIGHLY
PENETRANT PHENOTYPES.
BUT WHEN YOU WHEN YOU LOOK AT A
QUALITATIVE TRAIT, YOU FIND A
COMMON VARIANT WHICH IS NOT
CODING WHICH APPEARS ACTUALLY TO
BE A VERY MINOR CONTRIBUTE OR
BUT IT'S REAL.
>> AND WE MAY STILL HAVE ONE
LIKE THAT WITH ADAM 10 AS WELL
BUT THIS LOOKS LIKE IT WAS
THERE.
>> MY QUESTION IS -- 
[INDISCERNIBLE]
CAN THESE MODULATORS OR DRUGS
COMPLETELY REDUCE THE TANGLES?
--
[INDISCERNIBLE]
>> THE PROBLEM IS WE DON'T HAVE
A MODEL TO TEST THAT.
OUR MOUSE MODELS ARE AMYLOID
MODELS.
WE DO NOT HAVE A MODEL.
IT'S TERRIBLE.
WE DON'T HAVE A MOUSE MODEL
WHERE YOU START WITH AMYLOID AND
GET TO A --
>>  [INAUDIBLE]
>> WE HAVE ONE WHERE YOU THROW
THE MUTATION IN AND YOU GET A
PATHWAY OF TANGLES AND BLACKS
BUT YOU DON'T HAVE BLACKS
DRIVING TANGLES WHICH APPEARS TO
BE HAPPENING IN THE HUMAN BRAIN.
THAT'S A BIG PROBLEM.
SO IT'S HARD TO TEST THAT.
>> SO DO YOU THINK THAT THESE
DRUGS WILL REALLY WORK FOR -- 
PATHOLOGIY?
>> I THINK IT'S A START.
I THINK IF YOU COULD REDUCE
AMYLOID LEVELS AND I WOULD ALSO
ARGUE REDISTRIBUTE THE METALS
THAT ARE SEQUESTERED ACCORDING
TO THAT HYPOTHESES, IT'S A
START.
I WORRY ABOUT THIS NEW DATA THAT
SUGGESTS THE PATHOLOGY CAN SAID.
IF THAT'S THE CASE, ONCE WE
START THAT PATHOLOGY, LET'S SAY
DROWN STREAM OF AMYLOID
ACCUMULATION, YOU CAN GET RID OF
THE AMYLOID AND FIX EVERYTHING
BUT IF THE PATHOLOGY KEEPS
SPREADING THEN WHAT?
AND IT LOOKS LIKE A LOT OF
GROUPS ARE CONFIRMING THAT, THIS
VERY SCARY NOTION THAT TAU
PATHOLOGY SPREADS.
SO YOU MAY NEED A COCKTAIL THAT
ALSO HITS THAT NOT JUST AMYLOID.
MAY NOT BE ENOUGH.
>> HI, I'M BURT GOLDEN NCI.
HAVING HAD DAVID GOLDSTEIN AND
YOU JUST ARGUE VERY STRONGLY
AGAINST COMMON VARIANT AND
FRANCIS TRYING TO COUNTER SOME
OF THAT, I JUST WANTED TO
PROVIDE TWO EXAMPLES FOR YOU
WHERE WE ARE PRETTY SURE THAT
THE ASSOCIATIONS REALLY DO NOT
RELATE TO THESE KINDS OF RARE
THINGS WHICH ARE FGFR2 AS A
MODIFIER GENE IN BREAST CANCER
WHERE EVERYTHING RELATES TO
INTRON 1 AND PROBABLY A
TRANSCRIPTION FACTOR BINDING
SITE AND EQ24, WHICH IS A GENE
DESERT THAT RELATES TO A GREAT
MANNY CANSERS AND HAS NO RARE
VARIANT, PER SE ASSOCIATED WITH
IT.
SO, I THINK THE JURY -- I THINK
IT'S FAIR TO SAY THAT THE JURY
IS STILL OUT ON THIS VERY
CONTENTS US ISSUE.
>> I SAID THAT.
I'M ARGUING HEAVILY ON THE RARE
VARIANT SIDE BECAUSE WE HAVE
BEEN SO TRAUMATIZED THAT THE
COMMON VARIANT, COMMON PARADIGM
HI TO GO OVERBOARD.
BUT I AGREE IT WILL BE A
COMBINATION THAT WE HAVE A
COMMON VARIANT WITH ANOTHER
COMMON VARIANT THAT HAS SOME
EFFECT ON THE SPECIALIST.
IT WILL BE A COMBINATION OF
THESE.
BUT YOU KNOW, WE RIGHT NOW ARE
GOING AFTER THE RARE VARIANTS
BECAUSE FRANKLY IF THEY HAVE
STRONGER EFFECTS, TO TEST IN
TRANSGENICS AND MORE OF THE LOW
HANGING FRUIT.
BUT THANK YOU FOR YOUR EXCEPT.
>> SO, AS MENTIONED, SO TAU
PATHOLOGY WHICH CORRELATES WITH
THE DEMENTIA AND IN YOUR
HYPOTHESES YOU SAY THAT THE TAU
PATHOLOGY IS ASSOCIATED WITH
EXTRACTION OF METALS ESSENTIALLY
COPPER, ZING.
>> THAT'S MY --
>> YES, THAT'S THE SAMELESS
SPECULATION.
THE QUESTION HERE IS, DO YOU
THINK OF THE TAU PATHOLOGY AS
BEING CAUSAL FOR THE DEMENTIA OR
SIMPLY A MARKER OF OTHER EVENTS?
BECAUSE FROM YOUR SEED
HYPOTHESES YOU MIGHT THINK THE
TAU PATHOLOGY IS A MARKER RATHER
THAN CAUSAL.
HOW ABOUT SHAMELESS SPECULATIONS
ON THAT PROBLEM.
>> SURE.
I DON'T KNOW.
I MEAN, I THINK KAREN'S PAPER
SHOWING THAT YOU HAVE GOT -- IN
TRANSGENIC MICE YOU HAD
COGNITIVE IMPAIRMENT WITH THE
PRESENCE OF TAU LIGAMENTS BEFOREj2S9AQ(o
TANGLES ARGUES YOU MAY NOT NEED
TANGLES THEMSELVES TO GET THERE.
THAT JUST TAU LIGMERS GET YOU
THERE.
SO IT'S VERY AKIN TO THE IDEA
YOU MIGHT NOT NEED PLAQUES BUT
YOU COULD JUST HAVE YOUR LIGMERS
GET YOU THERE.
SO THERE ARE PARALLEL SITUATIONS
FOR PLAQUES AND TANGLES.
LIGMERS MAY BE DOING THIS.
WE WON'T KNOW UNTIL WE GET THE
DATA IN AND BUT WHAT IS CLEAR
FROM NEUROPATHOLOGY IS THAT WHENg8mN+JWñ
WE HAVE A PATIENT WHO IS NOT
DEMENTED WITH A HEAD FULL OF
AMYLOID, THAT MEANS THEY DIDN'T
HAVE TANG ELSE.
THAT'S WHAT WE NEED TON.
>> SO LET ME INVITE WHO YOU ARE
INTERESTED TO COME TO THE
LIBRARY FOR COFFEE AND COOKIES
AND FURTHER CONVERSATION.
LET'S THANK OUR SPEAKER AGAIN.
LET'S THANK OUR SPEAKER AGAIN.