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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)
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
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
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
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
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
Anti-AmyloidTreatmentinAsymptomaticAlzheimer’sDisease
• NORMAL65-85yearoldadults
• EvidenceofADpathologyinbrainscans
• GoaltopreventorslowAD
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/