Progress in Treatment and Prevention of Alzheimer’s Disease

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Progress in Treatment and Prevention of Alzheimer’s Disease SNUCMAA 2016 Annual Meeting June 4, 2016 James J. Lah, MD, PhD

Transcript of Progress in Treatment and Prevention of Alzheimer’s Disease

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

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

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/