Effects of traumatic brain injury (TBI) & post traumatic stress disorder (PTSD) on Alzheimer’s disease (AD) in Veterans using ADNI (DOD ADNI) Michael W. Weiner

ALZHEIMER’S DISEASE An amyloid-β facilitated tauopathy Synapse loss, neurodegeneration associated with progressive memory problems leading to dementia Dementia due to AD, MCI due to AD, preclinical AD. No disease modifying treatment/prevention AD runs in families and APOE4 is a major risk factor. Other genes involved AD commonly occurs with other pathologies Many treatment trials, mostly aimed at Aβ All failures, but recently…..

BIOGEN STUDY Pre-specified Interim Analysis: A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease Jeff Sevigny,1 Ping Chiao,1 Leslie Williams,1 Tianle Chen,1 Yan Ling,1 John O’Gorman,1 Jim Ferrero,1 Alvydas Mikulskis,1 Christoph Hock,2 Roger Nitsch,2 Alfred Sandrock1 1Biogen Idec, Cambridge, MA, USA; 2Neurimmune Holding AG, Zurich Sevigny J, Chiao P, Williams L, et al. A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease. Presented at: 12th International Conference on Alzheimer's and Parkinson's Disease. Mar 18– 22, 2015 Nice, France. Educational resource provided in response to unsolicited request (Content current 22-Mar-2015) BA-US-0072

STUDY DESIGN Sevigny J, Chiao P, Williams L, et al. A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease. Presented at: 12th International Conference on Alzheimer's and Parkinson's Disease. Mar 18– 22, 2015 Nice, France. BA-US-0072 Educational resource provided in response to unsolicited request (Content current 22-Mar-2015)

EFFECTS ON BRAIN AMYLOID Sevigny J, Chiao P, Williams L, et al. A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease. Presented at: 12th International Conference on Alzheimer's and Parkinson's Disease. Mar 18– 22, 2015 Nice, France. BA-US-0072 Educational resource provided in response to unsolicited request (Content current 22-Mar-2015)

CHANGE OF MINI-MENTAL STATE EXAM Sevigny J, Chiao P, Williams L, et al. A Randomized, Double-blind, Phase 1b Study (PRIME) of Aducanumab (BIIB037), an Anti-Beta-Amyloid Monoclonal Antibody, in Subjects with Prodromal or Mild Alzheimer’s Disease. Presented at: 12th International Conference on Alzheimer's and Parkinson's Disease. Mar 18– 22, 2015 Nice, France. BA-US-0072 Educational resource provided in response to unsolicited request (Content current 22-Mar-2015)

John Hsiao, Neil Buckholz, Private Partners Scientific Board (PPSB) FUNDED BY NATIONAL INSTITUTE ON AGING NIBIB,NIMH,NINR,NINDS,NCRR,NIDA and CIHR M. Weiner, P. Aisen, R Petersen, C. Jack, W. Jagust, J Trojanowski, L. Shaw, A. Toga, L. Beckett, D. Harvey, R. Green, A Saykin, J Morris, N Cairns, L Thal (D) John Hsiao, Neil Buckholz, Private Partners Scientific Board (PPSB) Site PIs, Study Coordinators and over 1500 subjects enrolled in 58 Sites in US and Canada

ADNI2 Multimodality Neuroimaging Structural imaging T1weighted T2 weighted FLAIR DTI ASL MRI fMRI FDG PET Amyloid PET

RISK FACTORS FOR AD Age and family history (Apoe-4) !!! Traumatic brain injury, concussion Many others Obesity, diabetes, hypertension, cerebrovascular disease, stroke, low SES, low education, lack of exercise, smoking, etc. Including PTSD

BACKGROUND Many studies show an epidemiological association of TBI with dementia of the Alzheimer’s type Autopsy studies show an association of TBI with amyloid accumulation There has been no prospective study of TBI and PTSD on AD using biomarkers.

DEPARTMENT OF DEFENSE ADNI Study of 200 normal veterans over age 65 History of TBI, PTSD, or controls; 1 yr. F/U Study of 200 MCI veterans over age 65 Same groups: 1 yr. F/U Study almost identical to ADNI

METHODS Recruitment uses data-base provided by the Veterans Administration: Big Challenge Telephone screening before referral to sites Clinical/Cognitive assessment identical to ADNI. Additional assessment of PTSD LP/CSF identical to ADNI Imaging identical to ADNI: No FDG PET DTI, resting state fMRI, no perfusion MRI

Recruitment: Overall Summary 157 Subjects eligible for Baseline (150 Completed Baseline) 35% PTSD (n = 55) 12% TBI (n =19) 14% Both (n = 22) 39% Controls (n = 61) 252 Clinic Referrals 12% In Process 62% Baseline 26% Exclude/Withdraw 376 SCID Referrals 6% Pending 67% Referred to Clinic 27% Exclude/Withdraw 798 Consents Sent; (478 Signed and Returned) 41% Waiting 47% Received; OK for SCID 12% Exclude/Withdraw 3,508 Completed Screens 23% Mailed Consents 77% Excluded 10,400 Subjects Called 37% Pending 34% Complete Screen 29% Decline 12,867 Brochures Mailed 83% No Response 13% Respond “Yes” 4% Opt Out

Recruitment: Race & Ethnicity Totals Caucasian African American “Other” Race Missing from VA C&P Latino / Hispanic Not Latino / Hispanic Missing from VA C&P USA Census Population (2012 estimate) 313,873,685 77.9% 13.1% 9.0% N/A 16.9% 83.1% Sample of Vietnam Veterans (VA Comp. & Pension) 67, 925 61.7% 17.8% 3.0% 17.5% 3.8% 78.4% Mailed Brochures 12,867 44.3% 17.3% 2.9% 35.5% 4.5% 59.6% 35.9% Subjects Called 10,400 46.4% 19.8% 2.8% 30.9% 64.4% 31.2% Baseline 157 83.4% 7.0% 9.6% 10.2% 89.8%

Subjective Memory Complaints of 157 Baseline Subjects (w/AD8)

Cognitive Status at Clinic Baseline Cohort % Normal % MCI Controls (n=55) 96.4% (n=53) 3.6% (n=2) PTSD (n=51) 86.3% (n=44) 13.7% (n=7) TBI (n=19) 89.5% (n=17) 10.5% (n=2) Both (n=21) 81.0% (n=17) 19.0% (n=4) Total (n=146) 89.7% (n=131) 10.3% (n=15)

Reasons for Exclusion at Pre-Screen

CONCERNS Small % of subjects contacted agreed to participate: Very arduous study High screen-fail rate More drop out as subjects were asked to make clinic visits: Reflects arduous study Only a small fraction of Vietnam subjects with TBI and PTSD participate: Generalizability?

Successes; Data Analysis Begun: Florbetapir summary N=99 80/266 AV45+ (30%) 10/42 AV45+ (24%) A B Cortical florbetapir retention (whole cereb ref) 3/31 AV45+ (10%) 4/15 AV45+ (27%) 3/11 AV45+ (27%) 42 70.4 26% 266 75.6 26% 31 67.8 23% Total N 99 N Age % ApoE4+ 15 67.0 31% 11 66.7 29% S Landau 12.16.14

A: 66 year old male TBI patient

B: 68 yrs. male TBI patient

SUMMARY AND CONCLUSIONS This study demonstrates some of the problems with recruiting veterans into AD research trials: high levels of excludes More MCI in PTS and TBI groups Thus far, the results show no effects of TBI or PTSD on AD measured with biomarkers We are not even 50% enrolled yet High excludes and low minorities emphasizes the problems of biomarker-intensive studies Emphasizes challenges of clinical trials on veterans

An online registry for recruitment, screening, and monitoring progression of neurodegenerative diseases Available to investigators for all types of neuroscience studies. Goals” To accelerate neuroscience research: To establish a large cohort of participants who are monitored longitudinally To provide a pool of eligible participants to other investigators to facilitate their studies by creating a new model of recruitment and screening To establish large cohort of TBI/PTS subjects To accelerate the development of treatments by facilitating clin trials, we developed pool+: BHR uses an economy of scale. Traditionally, each clinical trial recruits separately. They may use online,, web-based prescreen tools. But BHR creates a pre-existing, pre-screened pool of potential subjects

How it works Showcasing a recent PR effort involving B. Smith, a celebrity spokesperson recently diagnosed with late-onset AD Anyone can go to the website and sign up, not disease specific, although we do a lot of targeted PR/advertising for older adults at risk for AD.

The Brain Health Registry: How it Works UCSF IRB approved; Obtain online consent from all participants Sign up Tell us about yourself Take some tests take out small text under each number. Streamline. Mention Cogstate and Lumos. Put the cogstate slide right after this. Come back Come back…again

The Brain Health Registry: How it Works UCSF IRB approved; Obtain online consent from all participants Sign up Self-reported memory problems, family history of AD, health and lifestyle Tell us about yourself Take some tests take out small text under each number. Streamline. Mention Cogstate and Lumos. Put the cogstate slide right after this. Come back Come back…again

The Brain Health Registry: How it Works UCSF IRB approved; Obtain online consent from all participants Sign up Self-reported memory problems, family history of AD, health and lifestyle Tell us about yourself Take some tests Online cognitive tests from Cogstate, Ltd. and Lumosity, Inc. take out small text under each number. Streamline. Mention Cogstate and Lumos. Put the cogstate slide right after this. Come back Come back…again

The Brain Health Registry: How it Works UCSF IRB approved; Obtain online consent from all participants Sign up Self-reported memory problems, family history of AD, health and lifestyle Tell us about yourself Take some tests Online cognitive tests from Cogstate, Ltd. and Lumosity, Inc. take out small text under each number. Streamline. Mention Cogstate and Lumos. Put the cogstate slide right after this. Come back Participants return and repeat tasks every 6 months Come back…again

Cogstate Brief Battery: 4 Card tests measuring cognitive function across various domains Supervised version has clinical validity, reliability, sensitivity to age effects Has been used in MCI subjects Longitudinal decline can predict amyloid positivity Online cog. Tests are provided by 2 partners: Cogstate, and Lumosity. Cogstate: Australian, pioneer in computerized cog. Testing 195 subjects: study eligibility required individuals to be age 50 years or older, healthy, community dwelling and willing to be informed of possible cognitive decline. Exclusion criteria included self-reported pre-existing cognitive impairment, and neurological or psychiatric disease. For the current study, subjects were required to have completed at least the baseline, 12-, and 24-month assessments. Chen et al 2010; Lim et al 2012, 2013; Darby et al 2011, 2012, 2014

Lumos Labs: Sharing Contacts & Data 11/23/11 Lumos Labs: Sharing Contacts & Data

Growth of the Brain Health Registry Over 31,000 participants registered in 18 months 95% say they are willing to be contacted for future studies 49% of registrants return for 6 month follow-up (since October 2014) 37% of registrants return for 1 year follow-up (since April 2015) 57% of returners complete all follow-up tasks The cohort of “returners” is enriched in older subjects with memory concerns ***If possible, turn this into a visual timeline Encouraging for feasibility of collecting long. Data from a large cohort with very few incentives. Major goal is to recruit for Ad studies….do we have eligible subjects? Wanted to ask Can we make it…yes Can we get people to join…yes Is the data we get valid/useful….we had concerns but surprisingly data is very good. Can we get eligible subs. For AD trials, the right subs in the right places….yes. how many subs will actually come to clinics for studies…possibly 1 out of 5.

SUMMARY BRAIN HEALTH REGISTRY BHR is available to investigators for recruitment, assessment, longitudinal monitoring of subjects Can be used to study TBI, PTS, cognitive problems, emotional problems, genetics Not a substitute for in-clinic assessments Scalability leads to low costs