Progress in Treatment and Prevention of Alzheimer’s Disease
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)
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/