1. Alzheimer’s Disease Neuroimaging Initiative Neuropathology Core John C. Morris, MD Nigel J. Cairns, PhD, FRCPath Erin Franklin, MS Presented by: Beau Ances, MD, PhD (Washington University ADNI site PI)

2. Table 1. Participants Autopsied per Funding Period Note: The ADNI-NPC was established on 9/1/2007. ADNI Funding Period ADNI-NPCDeathsAutopsies Annual Autopsy Rate (%) 9-1-05 to 8-31-07NO600 9-1-07 to 8-31-08YES7228 9-1-08 to 8-31-09YES88100 9-1-09 to 8-31-10YES4125 9-1-10 to 8-31-11YES13646 9-1-11 to 8-31-12YES4375 9-1-12 to 8-31-13YES15853 9-1-13 to 8-31-14YES201365 9-1-14 to 3-31-15YES9667 Total (2005-2015)-864754 Total since NPC established-804759

3. Table 2. Clinical and Neuropathologic Diagnoses at Expiration Clinical Dx at Expiration ADNI: Neuropathologic Diagnosis [N (%)] TOTAL (%) ^ AD +DLB AD +TDP AD +DLB +TDP AD+ DLB +TDP+AGD AD +ALB+TDP AD + AGD AD + ALB AD +HS +AGD AD +TDP +Infarcts AGD Pending DAT16*10** 2 1122†12*** 37 (79) DAT+DLB 111 3 (6) Pending 7 7 (15) TOTAL (%) ^ 16 (34) 10 (22) 2 (4) 2 (4) 1 (2) 1 (2) 1 (2) 2 (4) 2 (4) 1 (2) 2 (2) 7 (15) 47 (100) AD, Alzheimer disease (NIA-AA score: A1, B0, C0 or greater); ALB, AD with amygdala Lewy bodies; DLB, dementia with Lewy bodies; AGD, argyrophilic grain disease; TDP, AD with TDP-43 proteinopathy in medial temporal lobe; HS, hippocampal sclerosis. Note:*One case had additional infarcts; **One case had additional AGD; †One case had additional TDP-43 proteinopathy; ***Both cases had additional tangles in the medial temporal lobe; ^Figures are rounded and may not equal 100%. Small vessel disease (arteriolosclerosis and cerebral amyloid angiopathy) was a feature of all cases. Mean age at expiration 81.2 (range: 59-93) 7 assessments pending

4. Table 3. Comorbidities in AD in ADNI and Dominantly Inherited Alzheimer Network (DIAN) Participants Neuropathologic DiagnosesLOAD (ADNI)ADAD (DIAN) PrimaryComorbidities^N=40*%N=22**% ADNone1640.01150 ADDLB/ALB1640.011†50 ADTDP-43820.000 ADAGD512.500 ADHippocampal sclerosis25.000 ADInfarcts25.000 AGDNone25.000 *7 cases pending; **2 cases pending; ^more than one comorbidity may be present in a single case; †, one case had additional glioblastoma multiforme. l Average age at death = 81.2 y (ADNI) and 51.6 y (DIAN) l Of 33 ADNI cases with expiration CDRs, 5 were CDR 0.5, 3 were CDR 1, 8 were CDR 2, and 17 were CDR 3 l Of 7 DIAN cases with completed assessments, all were CDR 3 Nigel Cairns, In Press

5. Proposed ADNI-3: Neuropathology Core Aims Aim 1: To foster and facilitate a voluntary brain autopsy for each deceased ADNI participant; Aim 2: To provide a uniform neuropathologic assessment in all autopsied ADNI participants; Aim 3: To investigate the relationship between the molecular neuropathology, structural, and functional changes in early AD; Aim 4: To maintain a repository of frozen and fixed brain tissue from ADNI participants to facilitate ADNI investigator-led research; Aim 5: To test the hypothesis that comorbidities (Lewy bodies, TDP- 43 proteinopathy, vascular disease, hippocampal sclerosis, and argyrophilic grain disease) contribute to the variance in clinical, CSF biomarker, and neuroimaging data.

6. How ADNI 1/2/GO Data Have Influenced the ADNI-NPC Proposed Aims for ADNI-3 l Biomarker data (structural and functional neuroimaging and CSF) indicate that comorbidities (Lewy bodies, TDP-43 proteinopathy, and vascular disease) in LOAD are: 1) detectable, and 2) contribute to the variance in ADNI biomarker data. l Data collected will facilitate multiregional and multimodal clinico-biomarker-neuroimaging- neuropathologic correlations.

7. Reminders about Autopsy Consent/Brain Donation l Neuropathology remains the gold standard for diagnosing dementing diseases. Neuropathologic data permit multimodal and genetic studies of these comorbidities to improve diagnosis and provide etiologic insights. l All ADNI participants should be asked to consider brain donation. The ADNI Neuropathology Core Coordinator, Erin Franklin (efranklin@path.wustl.edu), will assist in establishing the protocol and/or finding autopsy services for all sites.efranklin@path.wustl.edu l Where a participant dies does not prevent ADNI an autopsy. We can find autopsy services almost anywhere! l If a participant donates his or her brain to another program (eg, an ADC Neuropatholgy Core), the ADNI NPC will arrange tissue sharing with that program.

8. Reminders –II. l Please follow up with participants who are undecided about autopsy consent. Frequently update the participant’s and next-of-kin’s contact information and let the NPC know if any change in autopsy services is required. l Notify the ADNI Neuropathology Core (available 24/7: 314-362-8079; after hours pager 314-841-4738) as soon as the participant dies. This information is needed for our records regardless of whether an autopsy is being performed. l Please communicate with the Neuropathology Core Coordinator prior to shipping the brain tissue. We need certain information to receive tissue in our Neuropathology Division at Washington University School of Medicine, and also need information regarding the participant’s cause of death and estimated CDR at the time of death that cannot be obtained from ADNI study records.

9. Reminders –III. l Please do not have a participant believe that their wishes regarding brain donation will be carried out unless arrangements have been made. l If you have ANY questions related to brain donation, autopsy, or reimbursable autopsy expenses, please ask. We are only an e-mail or phone call away (314-362-8079; after hours pager 314-841-4738; efranklin@path.wustl.edu) efranklin@path.wustl.edu

10. l ADCS will be sending out a follow-up memo to this presentation on behalf of the NPC in the coming month. Please look it over and contact us if there are any questions. Note