Alzheimer’s Disease Neuroimaging Initiative STEERING COMMITTEE April 20 2015 Michael W. Weiner

The “Big” News The highly encouraging Biogen phase 1b results, showing reduction of brain amyloid load and slowing of cognitive decline, provide POC for anti-amyloid treatments This encourages more clinical trial activity more NIH funding interest in AD biomarkers detection and monitoring Potential problems in enrolling ADNI 3 subjects

THE BIG PICTURE Overall, ADNI is doing very well We have 15 months left for ADNI2 Two tau PET studies funded in past year DOD Tau PET, includes ADNI subjects ADNI competitive supplement for tau PET Should allow tau PET on all ADNI and DOD ADNI subjects and longitudinal studies Expect to submit ADNI3 mid October 2015

PLANS FOR ADNI 3 SPECIFIC AIMS Overall goal: validation of biomarkers for AD Longitudinal change of cognition and biomarkers: measures that capture longitudinal change with highest statistical power Prediction of cognitive decline: Clinical trial design: Optimum outcome measures, predictors, and inclusion/exclusion criteria for clinical trials Discovery: new markers, new targets

ADNI 3 STUDY DESIGN About 900 subjects planned 40% cognitively normal, 40% MCI, 20% dementia (from converted MCI) Most subjects will be roll-overs, but some new subjects will be enrolled Annual visits: Clinical, cognitive, MRI, amyloid PET, tau PET, FDG PET?, LP/CSF, genetics, omics

NEW FEATURES IN ADNI 3 Use of Brain Health Registry for recruitment, assessment and longitudinal monitoring Includes on-line cognitive testing for screening, F/U Tau PET: AVID 1451, and others to be considered Amyloid PET centaloid project: AVID, Pirimal, ? Advanced, Connectome, multi-modal MRI New Platform for CSF analysis, Mass Spec Systems Biology, Omics, and Data Mining

DISCLOSING RESULTS TO PATIENTS Some clinicans request to disclose results to patients. Request change in ADNI policy Advantages Patients have a “right to know” Will facilitate recruitment/retention Disadvantages This action will change the outcome Not using “CLIA-approved labs” Amyloid PET, CSF results, tau results, genetics? Current plan is not to include in grant application

PROBLEM: COMPETITIVE SPACE Selection of ADNI 3 Biomarker platform Review of all possibilities: consultation with PPSB Selection of tau tracer by PET Core Currently AVID 1451 is only tracer widely available, piloted in ADNI2 All possible tau tracers to be considered Selection of on-line cognitive tests Compelling data in grant required: goal is to be funded ADNI 3 begins 16 months after grant submission ADNI 3 enrollment will compete with many trials

COLLABORATION WITH INDUSTRY PARTNERS ADNI is a grant submitted to NIA, must be reviewed and funded ADNI investigators responsible for scientific conduct UO-1 or UO-19 requires close NIA oversight: For example, NIA decides on sample release Industry supports 30% of funds. The overall goal is to facilitate industry and academic trials. We greatly value PPSB input and collaboration

OTHER COLLABORATIONS Joint analysis with DIAN Joint analysis of ADNI and PPMI data sponsored by Michael J Fox SAGE Challange

GOVERNANCE Grant is submitted to NIA from the Northern California Institute for Research and Education (NCIRE), Michael Weiner PI In the event that the PI cannot function as PI, Bill Jagust , at UC Berkeley, will become PI and assume an NCIRE appointment After that future decisions will be made by NIA, NCIRE, ADNI Executive Committee , in consultation with the PPSB

LONG TERM FUTURE OF ADNI If ADNI 3 proceeds, what would happen after ADNI 3? Depending on success of treatments, it may not be possible to enroll subjects with preclinical, prodromal or , dementia due to AD in an observational trial Shift to study of younger amyloid negative subjects at long term risk for developing amyloid positivity: primary prevention trials to prevent amyloid /tau formation And/or a study of “normal aging”

OPPORTUNITY ADNI 3 may be the “last” large observational study of the natural history of AD progression Availability of treatments will prevent study of populations without treatment High excitement about AD clinical trials provides compelling rationale for ADNI3 to inform better trial design

MANY THANKS NIA for strong support Industry Partners, Foundations, and FNIH Site PIs, study coordinators ADCS staff Subjects and their families