INTRODUCTION: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals. METHODS: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. RESULTS: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 22[95%CI 13,46], cortical PIB 32[20,57], CSF p-tau181 58[40,112]) for a four-year trial to have 80% power (5% statistical significance) to detect a 25% reduction in absolute levels of pathology, allowing 40% dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50% reduction in rate of change. Sample sizes ranged from 75-250 (examples precuneus volume: 137[80,284], cortical FDG: 256[100,1208], CDR-SB: 161[102,291]). DISCUSSION: Despite the rarity of ADAD, clinical trials with feasible sample sizes given the number of cases appear possible.

JJLG is supported by NIH-NIA (K01AG073526), the Alzheimers Association (AARFD-21-851415, SG-20-690363), the Michael J. Fox Foundation (MJFF-020770), the Foundation for Barnes Jewish Hospital and the McDonnell Academy. EMD received support from the National Institute on Aging, an anonymous organization, the GHR Foundation, the DIAN-TU Pharma Consortium, Eli Lilly, and F Hoffmann La-Roche; has received speaking fees from Eisai and Eli Lilly; and is on the data safety and monitoring board and advisory boards of Eli Lilly, Alector, and Alzamend. GD reports no competing interests directly relevant to this work. His research is supported by NIH (K23AG064029, U01AG057195, U01NS120901, U19AG032438). He serves as a consultant for Parabon Nanolabs Inc and as a Topic Editor (Dementia) for DynaMed (EBSCO). He is the co-Project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from NINDS (U01NS120901) and Amgen Pharmaceuticals; and a consultant for Arialys Therapeutics. He has developed educational materials for Continuing Education Inc and Ionis Pharmaceutical. He owns stock in ANI pharmaceuticals. Dr. Day's institution has received support from Eli Lilly for development and participation in an educational event promoting early diagnosis of symptomatic Alzheimer disease, and in-kind contributions of radiotracer precursors for tau-PET neuroimaging in studies of memory and aging (via Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly). PRS receives funding from the National Health and Medical Research Council (Australia) grants 1176716 and 2022057 and the Medical Research Future Fund (Australia) grants 1200428 and 1200428. He is a director (unpaid) of the Australian Dementia Network Ltd. RJB, Professor of Neurology at Washington University School of Medicine (WUSM) receives lab research funding from the National Institutes of Health, Alzheimers Association, BrightFocus Foundation, Rainwater Foundation, Association for Frontotemporal Degeneration FTD Biomarkers Initiative, Tau Consortium, Novartis, Centene Corporation, Association for Frontotemporal Degeneration, the Cure Alzheimers Fund, Coins for Alzheimers Research Trust Fund, The Foundation for Barnes-Jewish Hospital, Good Ventures Foundation, DIAN-TU Pharma Consortium, Centene Corporation, Tau SILK Consortium (AbbVie, Biogen, Eli Lilly and Company and an anonymous organization), the NfL Consortium (AbbVie, Biogen, Bristol Meyers Squibb, Hoffman La Roche, and an anonymous organization). RJB has received honoraria as a speaker/consultant/advisory board member from Eisai, F. Hoffman-LaRoche, Janssen, Biogen; and reimbursement of travel expenses from Korean Dementia Association, American Neurological Association, Fondazione Prada, Weill Cornell Medical College, Harvard University, CTAD, FBRI, Beeson Foundation, Adler, Alzheimers Association Roundtable, Duke Margolis Roundtable, Bright Focus Foundation, Tau Consortium Investigators, NAPA Advisory Council on Alzheimers Research. RJB serves as principal investigator of the DIAN-TU, which is supported by the Alzheimers Association, GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium (Active: Biogen, Eisai, Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, and Janssen. Previous: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience). The DIAN-TU-001 Clinical Trial is supported by Pharmaceutical Partners Eli Lilly and Company, F. Hoffman-La Roche and Janssen, the Alzheimers Association, NIH U01AG042791, NIH U01AG42791-S1 (FNIH and Accelerating Medicines Partnership), NIH R01AG046179, NIH R56AG053267, NIH R01AG053267, NIH U01AG059798, NIH R01AG068319, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous organization. In-kind support has been received from CogState, Cerveau, Signant Health and Eisai Corporation. RJB is a co-founder of C2N Diagnostics and receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University (WU) has equity ownership interest in C2N Diagnostics. C2N Diagnostics will be analyzing samples from the Knight Family DIAN-TU-001 trial of E2814 for primary, secondary, and exploratory endpoints. Should the DIAN-TU trials impact the value of C2N Diagnostics, WU and RJB could directly benefit. NCF reports consulting fees from Biogen, Eisai, Ionis, Lilly, Roche/Genentech, and Siemens paid to UCL; he has served on a Data Safety Monitoring Board for Biogen; he acknowledges grant support from the Alzheimers Society, Alzheimers Research UK, Rosetrees Trust, the Sigrid Rausing Trust, the UK Dementia Research Institute and the UK NIHR UCLH Biomedical Research Centre. All other authors have no competing interests to disclose.

Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer's Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, the Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (HU21C0066) and the Instituto de Salud Carlos III, Spain (grant number 20/00448 to RSV). DMC work is supported by the Alzheimer's Society(AS‐PG‐15-025), UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK, Alzheimer's Association (SG-666374-UK BIRTH COHORT) and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre KEM was supported by an MRC skills development fellowship MR/P014372/1.

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The Institutional Review Board (IRB) of Washington University School of Medicine in St. Louis approved the study with the IRB ID# 201106339, and research was performed in accordance with the approved protocols The Ethics Committee of University College London (South Central-Berkshire ethics committe) gave ethics approval for this work under reference 09/HA0505/73.

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