©2012 MFMER | ADNI Clinical Core Paul Aisen Ron Petersen Michael Donohue Jennifer Salazar

ADNI 2 Enrollment Update ADNI2 enrollment closed - July 1, 2013 New ADNI2 subjects enrolled: 767 (not including baseline fails) ADNI 1 continuations to ADNI 2: 276 ADNI GO continuations to ADNI 2: 120 Total Enrolled in ADNI 2: 1,033 ((767 totaled enrolled in ADNI reported discontinuations) ADNI1 rollovers ADNIGO rollovers) ©2012 MFMER |

©2012 MFMER | ADNI2 Cumulative Enrollment by Cohort – April 2014

©2012 MFMER | CN n=184 SMC n=103 EMCI n=301 LMCI n=160 AD n=142 Combined n=891P Age (yrs) 73.4 (6.3) 72.2 (5.6) 71.3 (7.4) 71.9 (7.7) 74.6 (8.1) 72.5 (7.3) <0.001 Female 94 (51%) 61 (61%) 132 (44%) 75 (47%) 57 (40%) 419 (47%) Education 16.5 ( 2.5) 16.7 (2.6) 16.0 (2.7) 16.5 (2.6) 15.8 (2.6) 16.3 (2.6) CDR-SB 0.0 (0.1) 0.01 (0.2) 1.3 (0.8) 1.8 (1.0) 4.5 (1.7) 1.5 (1.7) <0.001 ADAS (4.5) 8.7 (4.3) 12.7 (5.4) 18.8 ( 7.1) 31.0 (8.3) 15.5 (9.6) <0.001 MMSE 29.0 (1.3) 29.0 (1.2) 28.3 (1.6) 27.6 (1.8) 23.1 (2.1) 27.6 (2.6) <0.001 Part. ECog 1.3 (0.3) 1.6 (0.3) 1.8 (0.5) 1.9 (0.6) 1.7 (0.5) <0.001 Study Part. Ecog 1.2 (0.3) 1.3 (0.3) 1.6 (0.5) 1.9 (0.7) 2.7 (0.7) 1.7 (0.7) <0.001 ADNI GO + 2 Baseline

ADNI 1+ GO + 2 Projected Dropouts ©2012 MFMER | NCEMCILMCIAD Reported 5%7%13%19% 14 months* 11%13%19%21% *projections include reported dropouts and late data entry; assumes 14 months late in data entry = dropout

©2012 MFMER | Assumes no data in 14 months = dropout

©2012 MFMER | Assumes no data in 14 months = dropout

©2014 MFMER | Dx ADAS CNSMCEMCILMCIAD MMSE Dx 21 CNSMCEMCILMCIAD CDRSB Dx 0 CNSMCEMCILMCIAD

©2014 MFMER | ECog Self Total Dx CNSMCEMCILMCIAD Dx CNSMCEMCILMCIAD ECog Partner Total

©2014 MFMER | ECog Total Dx Self Partner CN SelfPartner SMC SelfPartner EMCI SelfPartner LMCI SelfPartner AD 4

©2014 MFMER | Participant Study partner ECog Memory Score Count Dx (corr) CN (0.34) SMC (0.25) EMCI (0.25) LMCI (0.28) AD (-0.01)

©2014 MFMER | Study partner Participant ECog Total Score Count Dx (corr) CN (0.40) SMC (0.27) EMCI (0.23) LMCI (0.24) AD (0.18)

©2014 MFMER | ADAS 13 ADAS 13 change Month -5 0 Mean and 95% CI AD LMCI EMCI SMC CN

©2014 MFMER | MMSE MMSE change Month -2 0 Mean and 95% CI AD LMCI EMCI SMC CN

NL to MCI (1+GO+2)* ©2012 MFMER | * Imputed baseline AV45 where not observed

NL to MCI (GO+2) ©2012 MFMER |

EMCI to AD (GO+2) ©2012 MFMER |

LMCI to AD (1+GO+2) ©2012 MFMER |

LMCI to AD (GO+2) ©2012 MFMER |

ADNI3 CLINICAL CORE Paul Aisen Ron Petersen Mike Donohue Mike Weiner

ADNI3 Primary Aim  Validate biomarkers for clinical trials  To guide ADNI3, we need to reach consensus on the direction of future AD trials

ADNI3 additional goals  Address gaps in our understanding of the clinical spectrum of AD  Utilize biomarker advances (eg tau PET) to further elucidate AD neurobiology  Evaluate outcome measures, including computerized cognitive assessments  Facilitate new and promising trial designs

Focus on early stage disease?  Biggest gaps are early  Very early trials may be optimal for disease- modification. The likelihood of major, useful advances in AD dementia trials may be small.  There is certainly a need for drug development in AD dementia, including disease-modifiers, cognitive enhancers and behavioral therapies. But such trials are based on clinical/cognitive/behavioral measures that are fairly well established.

ADNI2 cohorts  Normal: CDR=0, no subjective complaints, LogMem nl, MMSE 24-30, age>=65 or 70 (adjusted periodically, wider range for minorities)  SMC: CDR=0, subjective complaints, LogMem nl, MMSE 24-30, age>=65 or 70 (adjusted periodically)  EMCI: CDR=.5, LogMem 1sd below norm, MMSE , age  LMCI: CDR=.5, LogMem 1.5sd below norm, MMSE , age  Mild AD: CDR=.5-1, dementia, LogMem 1.5sd below norm, MMSE 20-26, age 55-90

ADNI3 clinical trial aims  Study the utility of imaging and biochemical markers in prodromal and preclinical AD trials  Optimize cognitive and PRO-type measures in prodromal and preclinical AD trials  Facilitate primary prevention trials (?), ie, treatment before brain amyloid is elevated  This would be new territory and somewhat risky  In favor: primary prevention is the ultimate goal, and ADNI must lead the way  Against: Is industry interested? Can we find an efficient way to study individuals not yet at the preclinical stage?

These aims suggest:  Drop AD dementia from ADNI?  Continue indefinite follow-up of other existing ADNI2 cohorts  Add new biomarkers (tau PET)  Manage overall subject burden (drop FDG PET?)  Include: cognitive measures optimized for clinically normal subjects, computerized assessments, PROs, possibly explore functional performance testing  Reduce lower age limit (?)  Consider ways to enrich young normal for risk of AD (FHx, APOE, vascular risk, subjective concerns …)

Specific ideas for ADNI3  Drop AD dementia  Combine LMCI, EMCI  Reduce lower age limit on normal, but with enrichment based on risk  Focus on intermediate amyloid PET suvr group?

Example: new subjects for ADNI3 AgeCDRMemory concerns Risk Young normal at risk or -E4 carrier or known amyloid PET positive or CSF positive or strongly positive family history Normals or - MCI continue ADNI2 normal, SMC, EMCI, (LMCI?) drop ADNI2 AD cohort, subjects that have converted to AD dementia

Do we need younger subjects?  Perhaps: primary prevention will target middle age  Or: why not study transition to amyloid positivity in older individuals?

ADNI3 schedule, new and carry- over  Semiannual: mail-in assessments  Annual: MRI, blood, NP tests, computerized tests, PROs  Biennial: amyloid PET, tau PET, LP

Other ideas  Mild BehavioraI Impairment (Jesse Cedarbaum)  New biomarker approaches (ophthalmologic?)  Web-based recruitment/testing  Home-based (snail mail?) assessments  Utilize 23 and me data