Progress in Treatment and Prevention of Alzheimer’s Disease

SNUCMAA 2016 Annual Meeting

June 4, 2016James J. Lah, MD, PhD

TheDementiaEpidemic- AGlobalCrisis

$315billionannualcostsworldwideMoreexpensivethanheartdisease,cancer,andstrokecombined

2009WorldAlzheimer’sReportfromAlzheimer’sDiseaseInternational (ADI)

TheAlzheimer’sEpidemic

Arias, US Life Tables 2001

3.0% 18.7%

Evans et al. JAMA (1989)

47.2%

AgingandAlzheimer’sDisease

MildCognitiveImpairment

PatternsofCognitiveAgingCo

gnition

Age

Dementia

NormalAging

StagesofDementiaCo

gnition

PreclinicalStage MildDementia

ModerateDementia

SevereDementia

Age4550556065707580 85

MildCognitiveImpairment

End-stagecognitionDependentPoorqualityoflife

Profoundloss ofabilitiesBehavioralproblemsIncreasingburden

WorseningmemoryFunctionallimitationsNeedingmoresupport

IsolatedmemoryIndependentExcellentqualityoflife

Auguste D.andAlois Alzheimer

• Admitted1901,age51• FrankfurtamMain• Memoryloss• Languagedeficits• Persecutorydelusions• Progressivedecline

• Died1906,age55

PROGRESSINUNDERSTANDINGALZHEIMER’SDISEASE

Ø PathophysiologicalunderpinningsofAD

MultipleGeneticandEnvironmentalFactorsContributetoAlzheimer’sRisk

Genes EnvironmentRiskorProtective Factors

• AGE• Headtrauma• Depression• Hypertension• Cholesterol• Homocysteine• Ethnicdifferences• Education• Exercise• MediterraneanDiet• NSAIDS• Statins

GeneticsofAlzheimer’sDisease

EarlyOnset(<60)

FamilialAlzheimer’sDisease

Chrm21

APPPresenilins

PS1

Chrm 14

PS2

Chrm1

Mutations,RareAutosomalDominantGenes

LargeEffects(i.e,causativegenes)

LateOnset(>65)

Sporadic Alzheimer’sDisease

Chrm19

APOE

20+Loci

CLUCR1

PICALMBIN1ABCA7

CD33MS4A6ACDPA2MS4A6ESORL1

SNPs, CommonRiskFactorGenesSmallEffects

FamilialAlzheimer’sDisease

• Early-onset(<60y.o.)• Autosomal-dominant

inheritancewith100%penetrance

• Smallpercentageoftotalcases(<1%)

• Pathologyandsymptomssimilartosporadic,late-onsetcases

• Identifymolecularmechanismsandtherapeutictargets

FADPedigrees

Chrm21 Chrm14 Chrm1

βAPP PS1 PS2

AllknownpathogenicFADmutationsalterproductionofAβ peptidefrom

βAPP.

Beta-amyloidaccumulation

Hypothesis:TheaccumulationofextracellularamyloidinitiatesacascadeofeventsleadingtoneurotoxicityandclinicalsymptomsinAD.

AmyloidCascadeHypothesis

APP

α-secretase

amyloiddeposition

inflammationneuronloss

Dementianon-toxic

soluble

γ-secretase

Aβ

γ-secretasepresenilin

β-secretaseBACE

Beta-AmyloidPeptideProduction

ROLEOFBIOMARKERSINALZHEIMER’SDIAGNOSIS

Ø AccuracyofCSFassaysØ Invivoamyloidimaging

CSFBiomarkersofAlzheimer’sDiseaseu Beta-amyloid(1-42)u TotalTauproteinu Phospho-Tau

Blennow andHampel,LancetNeurol (2003)

CSFinClinicallyDiagnosedIndividualsu Sensitivity 90% (90/100positiveAD)u Specificity64% (41/114positiveNormal)u MCI: 72% (142/196positive)

ADNI;DeMeyeretal.,ArchNeurol (2010)

CerebrospinalFluidResultsPredictsProgressionfromMCItoAlzheimer’sDisease

Hanssonetal., LancetNeurol (2006)

Mormino,etal.,Brain (2009)

VisualizingADPathologyinLivingPeople

C PD9 frontal cortex D PD9 frontal cortex

A PD4 frontal cortex B PD4 hippocampus

BiomarkersandStagesofAD

ModifiedfromJacketal.,LancetNeurol (2009)

FROMUNDERSTANDINGTOTREATMENTS

Ø EmergenceoftheamyloidhypothesisØ Thefirstwaveofrationalanti-amyloidtherapeutics

Beta-amyloidaccumulation

Hypothesis:TheaccumulationofextracellularamyloidinitiatesacascadeofeventsleadingtoneurotoxicityandclinicalsymptomsinAD.

Corollary:Preventionofamyloidaccumulationwillsloworpreventthedevelopmentofsymptoms.

AmyloidCascadeHypothesis

Aβ

α-secretase

γ-secretasepresenilin

β-secretaseBACE

APP

Enhanceα-secretase

Blockβ-secretase

Blockγ-secretase

ClearAβ (vaccineandaggregationinhibitors)

AmyloidBasedTherapeuticTargets

Schenketal.,Nature (1999)

Schenketal.,Nature (1999)

PreventionofAmyloidPathology

AN1792 CaseReport

• AN-1792(A-betavaccine)– Halteddue toencephalitisin~6%

• CaseReport– 72yo womanwith5yearh/o AD– Received5dosesAN-1792– Sixweeksafterlastdoseconfused,

unsteady– Noresponse tosteroids,eventually

diedfromPE– Patchyresolution ofamyloid

Nicoll etal,NatMed (2003)

BiomarkersandStagesofADinClinicalTrials

Modified fromJacketal., LancetNeurol (2009)

EnrolledStudyParticipants

NAPAandtheNationalPlantoAddressAD

• NationalAlzheimer’sPlanAct– January2011– “anaggressiveandcoordinatednationalplantoattackAlzheimer’sdiseaseandimprovecareandservices”

• NationalPlantoAddressAlzheimer’sDisease– USDepartmentofHealthandHumanServices

• May2012,updatedJune2013

– Goal1:“preventoreffectivelytreatAlzheimer’sdiseaseby2025”

PotentialImpactofInterventions:5YearDelayReducesPrevalence&Cost~50%

1997 20072017 2027

2037 2047

U.S.PrevalenceofAD

(millions)

Brookmeyer etal., AmJofPublicHealth (1998)

Delay(years)

0

0.5

1

2

5

8

6

4

2

• Projectedtoincreaseto106.2millionby2050

• Delayingonsetby1yearwillsave12millionpeople

• Delayingonsetby2yearswillsave18millionpeople

• Mostdramaticreductioninlatestagedisease(16million)

Brookmeyer,International ConferenceonAlzheimer’sDisease (2007)

Cogn

ition

PreclinicalStage MildDementia

ModerateDementia

SevereDementia

Age4550556065707580 85

CurrentChallenges:EarlyDetectionandTreatment

DiseaseModifyingTherapies

DiseasePreventingTherapies

SymptomaticTherapies

DetectionofPreclinicalCSFChanges

Faganetal.,ScienceTransMed (2014)

Anti-AmyloidTreatmentinAsymptomaticAlzheimer’sDisease

• NORMAL65-85yearoldadults

• EvidenceofADpathologyinbrainscans

• GoaltopreventorslowAD

HealthyAging.emory.edu

Preventing Age-Related Diseases

Emory Healthy Aging Study: 100,000+ participants• Online consent and information; anyone over 18 eligible• Periodic surveys, cognitive games, mobile data collection

Emory Healthy Brain Study: 3,500+ participants• Face to face evaluation, blood, CSF, and other biospecimens, and brain MRI• Longitudinal assessment of individuals 50-70 years old

Intensive Data and Biospecimen Analysis (1,000)• The most comprehensive “omics” data set in existence for Alzheimer’s disease• Goal: identify accurate and predictive biomarker for AD

Earlier Detection and Prevention of Age-Related Diseases• Target ALL diseases: brain, heart, endocrine, cancer, musculoskeletal, etc.• http://healthyaging.emory.edu/