DIAN: Understanding AD in Persons with Causative Genetic

Mutations

John C. Morris, MDHarvey A. and Dorismae Hacker Friedman

Distinguished Professor of Neurology

24th Annual Southern California AD Research Conference

Disclosure Statement (2012-2013)l Sources of Research Support

1. National Institute on Aging (P50 AG05681; P01 AG03991; P01 AG026276; U19 AG032438)

2. Anonymous Foundation3. Alzheimer’s Association

l Consulting Relationships

1. Lilly USA

l Industry-Sponsored Trials

1. Janssen2. Pfizer3. Eli Lilly/Avid

Radiopharmaceuticals

� Fees > $10,000

None

� Stock Equity

None

� Speaker’s Bureaus

None

� Editorial Boards

Annals of Neurology

UCI MIND (Institute for Memory Impairments and Neurological Disorders)

l Founding Director, Carl W. Cotman, PhD, started the Institute in 1995; UCI Alzheimer’s Disease Research Center (ADRC) officially established in 2000 with Dr Cotman as Director

l Frank LaFerla, PhD, succeeded Dr Cotman as Director of the Institute and its ADRC in 2009

l Recognized for developing animal models of Alzheimer disease, exploring mechanisms (including exercise) to enhance successful aging, and establishing unique study populations (Down syndrome, the oldest old)

l Also notable because Dr LaFerla is known to prepare dinner for selected supporters!

Knight ADRC – Faculty and Staff (with gratitude to our participants and families!)

Knight ADRC – Faculty and Staff (with gratitude to our participants and families!)

David Holtzman, MD

Knight ADRC – Faculty and Staff (with gratitude to our participants and families!)

Randall Bateman, MD

My View of AD

l “Alzheimer disease” (AD) refers to the neurodegenerative brain disorder, regardless of clinical status, representing a continuous process of synaptic and neuronal deterioration

l AD has two major stages:– Preclinical (presymptomatic; asymptomatic), undetectable by current

clinical methods– Symptomatic (clinical)

l Symptomatic AD is defined by intraindividual cognitive decline, from subtle to severe, that interfers with daily function, and can be subclassified on symptom severity: – Incipient (prodromal; mild cognitive impairment)– Dementia

Morris JC, Arch Neurol 2012;69:700-708.

It is the best of times…l Most exciting research advances ever for AD

– Development of biomarkers for AD diagnosis and preclinical research

l Several promising therapeutic agents– Plans for secondary prevention trials

… it is the worst of timesl “Disease-modifying” drug trials all have failed

l Funding is critically needed, but in the US severe curtailment of NIH support for AD research

Failure of AD Candidate TherapeuticsAgent Target/Mechanism Outcome

Non-AβAtorvastatin; Simvastatin Cholesterol (HMG CoA reductase inhibitor) Negative

NSAIDs Inflammation Negative

Rosiglitazone Insulin (PPAR gamma agonist) Negative

Latrepirdine Mitochondrial function Negative

AβAN1792 Amyloid immunoRx Negative (AEs)

Tramiprosate Amyloid aggregation Negative

Tarenflurbil Gamma secretase Negative

Semagacestat; Avagacestat Gamma secretase Negative

Bapineuzumab Amyloid immunoRx Negative

Solanezumab Amyloid immunoRx Negative (+/-)

IVIG Nonselective immunoRx Negative

LY2886721 Beta secretase AEs

ACC-001 Amyloid immunoRx Negative

Preclinical and Symptomatic AD

Preclinical AD~20 y

No AD Symptomatic AD~7-10 y

Synaptic/Neuronal Integrity

↓ Hippocampal Volume

↑ CSF tau

+ Amyloid Imaging

↓ CSF Aβ42 TransitionPeriod

~5 y 0.5 à 1 à 2 à 3Cognitively Normal

↓ Cognition,↓ Metabolism,

and Other Potential

Indicators

Death

Tau

Microglia

Inflammation

Oxidative stress

Neuronal loss

CDR

Other

NIA-AA Diagnostic Guidelines for Dementia Due to AD (McKhann G et al, Alzheimer’s & Dementia 2011; 7: 263-269)

l Enhance diagnostic confidence for AD– Molecular biomarkers of AD

» Low levels of CSF Aβ42

» Elevated levels of CSF tau and phospho-tau» Amyloid imaging (PET tracers: 11C PIB, 18F Florbetapir, others)

– “Downstream” indicators of neurodegeneration» Reduced temporoparietal metabolism with FDG-PET» Whole brain and/or regional atrophy on MRI» (Disrupted connectivity on fMRI)

– Causative gene mutation (PSEN1, PSEN2, APP)» APOE4 insufficiently specific to be a diagnostic biomarker

Presymptomatic Detection of AD:Biomarkers (PIB Imaging)

Cognitively normal

Amyloid –

Cognitively normal

Amyloid +

Alzheimer dementia

Amyloid +

Courtesy of Mark A. Mintun and John C. Morris. Reprinted with permission. Copyright 2010 Washington University, St. Louis Missouri. All Rights Reserved

3 years later,Alzheimer dementia

0%

5%

10%

15%

20%

25%

30%

35%

50 55 60 65 70 75 80 85 90

Perc

ent w

ith A

myl

oid

Plaq

ues

Age

Percent of Cognitively Normal Participants with Amyloid Plaques

Courtesy of Mark Mintun, MD, and Andrei Vlasenko, PhD

Cross-sectional data Longitudinal data

Preclinical AD Stages and Symptomatic AD

Vos et al., Lancet Neurology 2013

Progression to CDR ≥0.5 DAT by Preclinical AD Stage

Vos et al., Lancet Neurology 2013

The Dawn of Clinical Amyloid Imaging Is Here

l Amyvid® (Florbetapir)– 18F tracer; FDA approved (2012) – commercially viable,

and may also replace 11C PIB in research

l Other 18F tracers in development, including by GE (Flutemetamol), Bayer (Florbetaben), and Navidea (NAV4694)

l Jan 2013: Medicare advisory panel voted to not cover costs of Amyvid®

– Insufficient evidence that it changes outcomes– July 2013: Original decision upheld; final decision

expected in October 2013

l Tau imaging– 18F-T807 and 18F-T808 recently acquired by Eli Lilly

from Siemens– Three 18F tracers in development by N Okamura

(Tohoku Univ, Sendai, Japan) in collaboration with V Villemagne (Univ Melbourne, Australia)

l Inflammation– PK11195, DPA-714, others

l Synuclein– Consortium to Develop an Alpha-Synuclein Imaging

Agent funded by the Michael J. Fox Foundation

Developing Molecular Imaging for Non-Amyloid Pathologies

Preclinical Alzheimer Diseasel ~30% of cognitively normal older adults have biomarker

evidence of preclinical AD

l Biomarker-positive CN persons are at increased risk of developing symptomatic AD compared with biomarker-negative CN older adults

l However, individual level prediction not currently possible– Is symptomatic AD inevitable?– If so, when will it develop?

l Asymptomatic AD mutation carriers are destined to develop symptomatic AD, and at about the same age as their affected parent

Introduction to Autosomal Dominant ADMeasure Autosomal

Dominant ADSporadic AD

Clinical presentation Amnestic Amnestic

Course

Gradual cognitive and functional decline, plus motor signs and seizures

Gradual cognitive and functional decline

MRI Hippocampal and whole brain atrophy

Hippocampal and whole brain atrophy

PIB PET Cortex plus basalganglia Cortex

FDG PET Parietal hypometabolism

Parietalhypometabolism

CSF Aβ 42 Decreased by 50% Decreased by 50%

CSF tau Increased by 2-fold Increased by 2-fold

Original DIAN Aims

l Determine WHEN the pathobiology of AD begins in asymptomatic mutation carriers in relation to parental age of onset of dementia

l Determine the SEQUENCE and RATE of the pathobiological changes

l Compare the clinical and pathological phenotypes of dominantly inherited AD with late onset AD

l Enroll and study longitudinally with a uniform protocol 400 persons (~200 MCs, ~200 NCs) from families with a known pathogenic mutation for AD

DIANCoordinating

CenterCore A: Administration

Morris

Core B: ClinicalBateman

Core D: Neuropath

Cairns

Core E: Biomarker

Fagan

Core C: Biostatistics

Xiong

Core F: GeneticsGoate

Core G: Imaging

Benzinger

Core H: Informatics

Marcus

External AdvisoryCommittee

Steering Committee(Core & Site Leaders,

FDA, Ethicist, Family Members, NIA, Other Key Personnel)

Clinical Coordinating

CenterAisenADCS

Wash.Univ

St. LouisBateman

UCLALos Angeles

Ringman

IndianaUniv

IndianapolisGhetti

ColumbiaUniv

New YorkMayeux

B&W; MGH

BostonSperling

Univ of MelbourneMelbourneMasters

Univ of New South Wales

SydneySchofield

NationalCell

RepositoryFor ADForoud

(NCRAD)

MRI Pre-Processing

MayoJack

(ADNI)

PET Pre-Processing

U MichKoeppe(ADNI)

Sub-Committees• Imaging Core Executive Committee• Resource Allocation Review

Univ of PittsburghPittsburghMcDade

Inst of Neurology

Univ CollegeLondonRossor

Edith Cowan UnivPerth

Martins

Butler Hosp Brown UnivProvidenceSalloway

Mayo-Jacksonville

Graff-Radford

University of Tübingen

JuckerDZNE

Ludwig-Maximilians-Universität

DanekDZNE

Dominantly Inherited Alzheimer Network (DIAN)*

*U19 AG032438 (JC Morris, PI)

Procedure Initial Visit

Follow-up Visit*

Study explanation XConsent XBlood for Genetic Analysis XBlood for Biochemical biomarkers X XInclusion and Exclusion Criteria XDemographics, Family History, Medical History, Physical Exam, Neurological Exam, UPDRS

X X

Clinical Evaluation – CDR, GDS, NPI, FAQ (Lifestyle),Hollingshead, Hachinski, Exercise questionnaire

X X

Psychometric Battery – MMSE, Logical Memory Test IA & IIA, Digit Span Test (forward and backward), Category Fluency Test, Trail Making Test (Parts A & B), Boston Naming Test, Letter Fluency, WAIS-R Digit Symbol, Word List Immediate and Delayed Recall, IPIP, Computerized Cognitive Battery

X X

MRI-3T X XFDG-PET X XPIB-PET X XLumbar Puncture for Cerebrospinal Fluid X X* Participants and collateral sources not seen annually have a yearly telephone interview

DIAN Assessments

DIAN Enrollment ReportOver Years 01-06, sites will recruit, enroll and follow these individuals to reach a sample size of 400 participants

Initial Visits Actual

Follow-up Visits

In-Person

Follow-up Visits

RemoteYear One (9/2008-6/2009) 11 0 0

Year Two (7/2009-6/2010) 76 0 5

Year Three (7/2010-6/2011) 103 26 39

Year Four (7/2011-6/2012) 79 57 92

Year Five (7/2012-6/15/2013) 67 75 103

YTD TOTALS 336 158 239

Participant Entry CharacteristicsAsymptomatic

244 (72.6%) Symptomatic

92 (27.4%)N = 336* (Target 80% Asymptomatic, 20% Symptomatic) (*Table based on 310 participants. 14 Mutations in Process- Missing)

MUT: 233 (72.4%) MUT: 89 (27.6%)

113 (NC-) 120 (MC+) 8 (NC-) 81 (MC+)

Age 39.1(SD 10.2)

35.2 (SD 9.1)

50.3(SD 12.4)

45.3(SD 9.7)

Gender (% Female) 58.2% 54.9% 75.0% 55.7%

Parental Age of Onset46.6

(SD 6.9)47.1

(SD 6.7)46.2

(SD 7.2)45.0

(SD 8.3)

Education14.7

(SD 2.6)14.6

(SD 2.8)12.5

(SD 3.4)13.5

(SD 2.6)

MMSE29.1

(SD 1.2)29.0

(SD 1.2)28.4

(SD 1.6)23.6

(SD 10.8)ApoE4+ 1 E4

2 E432 32 0 201 2 0 5

MC = Mutation Carrier; NC = Non-carrier*Table statistics based on 322 participants with NCRAD confirmed mutation data available as of 15 JUN 2013

Procedure Completion Rates(as of August 31, 2013)

Initial Visit Procedures Completed

TotalsN= 352

Psychometrics 347 (98%)Genetics Blood 352 (100%)MRI 330 (94%)PET PIB 314 (89%)FDG PET 318 (90%)Lumbar Puncture 291 (83%)Fasted Serum and Plasma 342 (97%)

DIAN Mutation Distribution

Gene Frequency

PSEN1 72.2%

PSEN2 8.7%

APP 19.1%

2:975-984.

Bateman et al., NEJM 2012

DIAN Clinical and Cognitive Data

l Significant differences in CDR-SB and MMSE scores are detected 5 years before expected symptom onset

l A significant difference in the delayed recall portion of the Logical Memory test is detected 10 years before expected symptom onset

Bateman et al., NEJM 2012

DIAN Imaging Data

l Significant differences in hippocampal volume and PET-PIB measures of precuneus Aβ deposition are detected 15 years before expected symptom onset

l A significant difference in FDG-PET measures of precuneus glucose metabolism is detected 10 years before expected symptom onset

Bateman et al., NEJM 2012

DIAN Biofluid Data

l Significant differences in CSF tau and Aβ42 are detected 15 years and 20-25 years, respectively, before expected symptom onset

l Plasma Aβ42 levels are elevated in mutation carriers, as compared with noncarriers

Alzheimer Biomarker Pathochronology in Autosomal Dominant AD

Morris et al., Clin Invest 2012; 2:975-984

DIAN Clinical Trials

l The 2007 RFA provided no funds for trials, but emphasized that the DIAN cohort “could serve as a population (for)… clinical trials funded by other mechanisms”

l The DIAN Clinical Trials Committee (CTC) formed in 2009 under the leadership of Randy Bateman– Members included DIAN investigators, a DIAN family member,

representatives from ADCS, NIA, and FDA

l In 2011, the DIAN CTC transitioned to the DIAN Trials Unit (TU), also led by Randy Bateman– Mission: design and manage interventional trials in DIAN

participants

DIAN Pharma ConsortiumDIAN-TU Director: Randy Bateman DIAN -TU Team: Virginia Buckles, Matt Carril, Dave Clifford, Angela Fuqua, Denise Levitch, JackiMallmann, Susan Mills, Angela Oliver, Anna Santacruz, Wendy Sigurdson, Christy Stewart, Joy Snider

DIAN Pharma Consortium

l Pharma companies collaborate with DIAN-TU and its academic institutions to advise on DIAN trials, nominate candidate drugs to be considered for DIAN trials, and support the DIAN-TU

l Currently, 10 companies comprise the PharmaConsortium (inaugural meeting July 2011)

l To date, 15 drugs have been nominated to DIAN-TU– DIAN-TU Therapy Evaluation Committee– Review criteria: safety data available (Phase II/III), engage

appropriate target, pipeline-ready

Randomization of MCs in DIAN Trials

DIAN Participants: 290Trial Eligible: 130

Additional Identified Potential Participants: 2,972

Randomization #1[to Arm A, B, or C; 1:1:1]

Total N = 240MC = 160NC = 80

Randomization #2[to drug or placebo; 3:1]

Drug BMC = 40

Drug CMC = 40

Drug AMC = 40

Pooled PlaceboMC = 40NC = 80

MC = 13NC = 27

Drug C ArmTotal N = 80

MC = 54NC = 26

Drug A ArmTotal N = 80

MC = 53NC = 27

Drug B ArmTotal N = 80

MC = 53NC = 27

MC = 14NC = 26

MC = 13NC = 27

DRUG TYPEBM

OUTCOME (TARGET)

BM OUTCOME (DOWNSTREAM)

Solanezumab(LILLY)

Anti-Aβantibody (soluble

Aβ)

CSF Aβ40, Aβ42

CSF tau, ptau181, PET

PIB, vMRI

Gantenerumab(ROCHE)

Anti-Aβantibody (fibrillar

Aβ)

PET PIBCSF Aβ40, Aβ42,

tau, ptau181, vMRI

LY2886721(LILLY)

BACE Inhibitor

CSF Aβ40, Aβ42

CSF tau, ptau181, PET

PIB, vMRI

• 2 yr treatment to BM outcome + 3 yr cognitive outcome for promising drug(s)• ADAD from DIAN and DIAN Expanded Registry, N=240 (mixed mutations)• N = 240 (160 MC, 3 drug arms + pooled placebo, 40 each; ~80 NC, placebo)• Age = -15 to +10 years compared to parental age of symptom onset

First Three Drugs in the DIAN Trial

On Hold

DIAN TU: “First Time Ever…”l Pharma companies collaborating to provide competing

investigational products in a single trial

l Two companies and WU agree on a single protocol, AND contracts completed between companies and WU in <1 year

l FDA approval for first ever anti-amyloid trial to prevent symptomatic AD with no protocol changes

l WU IRB approval on first submission (with no contingencies)

l Within 3 months from announcement of the trial drugs, the initial participant consented 12/31/12 and was randomized to treatment arm on 3/18/13 – first patient in!

l First ever trial in autosomal dominant AD has begun!!!– 9 participants now randomized– US/Canada Investigators Meeting held August 2013

DIAN Websitesl DIAN: www.dian-info.org

l DIAN Expanded Registry: www.DianXR.org(or 800-747-2979 toll free)

Knight ADRC – Faculty and Staff (with gratitude to our participants and families!)

Anne Fagan, PhD

Molecular Biomarkers Detect Symptomatic and Preclinical AD

l CSF signature of AD– Reduced Aβ42, elevated tau and p-tau

l Amyloid imaging – Pittsburgh Compound B (PIB), Amyvid (florbetapir)

l Strong inverse relationship between CSF Aβ42and PIB amyloid burden

l PIB amyloid burden increases as a function of the two known risk factors for AD: age and APOE4

Fagan et al., Ann Neurol 2006; Fagan et al., Arch Neurol 2007; Fagan et al., Ann Neurol 2009; Morris et al., Ann Neurol 2010