Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.

Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.
Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.
Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.
Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.
Competing Interests: Dr. Clifford Jack serves on an independent data monitoring board for Roche and has consulted for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Dr. Saykin receives support from Arkley BioTek (joint NIH SBIR grant); Avid Radiopharmaceuticals (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eli Lilly (collaborative research grant); and Springer‐Nature Publishing (Editorial Office Support as Editor in Chief, Brain Imaging and Behavior). Ophir Keret is an Atlantic Fellow for Equity in Brain Health and thanks the Global Brain Health Institute for supporting his work. Johannes Levin reports speaker fees from Bayer Vital and Roche; consulting fees from Axon Neuroscience; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; non‐financial support from Abbvie; and compensation for duty as part‐time CMO from MODAG, outside the submitted work. John C. Morris reports support from NIH grants P30 AG066444, P01 AG003991, and P01 AG026276 during the conduct of the study. He serves on the Editorial Boards of Brain & Life and Alzheimer's & Dementia. Su Yi was a paid consultant for Green Valley Pharmaceuticals LLC in 2018. Adam M. Staffaroni provides consultation to Takeda and receives research funding from the NIH, the Larry L. Hillblom Foundation, and the Bluefield Project to Cure FTD. Stephan Salloway reports grants, personal fees, and non‐financial support from Biogen; grants and personal fees from Eisai; grants, personal fees, and non‐financial support from Avid; personal fees and non‐financial support from Novartis; grants, personal fees, and non‐financial support from Lilly; personal fees from Genentech; personal fees and non‐financial support from Roche, outside the submitted work. Michael Weiner receives support for his work from the following funding sources: NIH, DOD, PCORI, California Dept. of Public Health, U. Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer's Association, The State of California, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI‐BHR), The Stroke Foundation, Fidelity Charitable, and the Veterans Administration. Dr. Weiner has served on advisory boards for Cerecin/Accera, Alzheon, Inc., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, National Institute on Aging (NIA), Boston University Alzheimer's Disease and CTE Center, MIRIADE at VUmc for Amsterdam UMC, Cytox, Indiana University, Acumen, Brain Health Registry and ADNI. He serves on the Editorial Boards for Alzheimer's & Dementia, TMRI and MRI. He has provided consulting and/or acted as a speaker/lecturer to Cerecin/Accera, Inc., Alzheimer's Drug Discovery Foundation (ADDF), BioClinica, The Buck Institute for Research on Aging, FUJIFILM‐Toyama Chemical (Japan), Garfield Weston, Baird Equity Capital, University of Southern California (USC), T3D Therapeutics, Cytox, Guidepoint, and Japanese Organization for Medical Device Development, Inc. (JOMDD). He holds stock options with Alzheon, Inc., Alzeca, and Anven. Bruce L. Miller reported serving on the advisory committee for Cambridge National Institute for Health Research Biomedical Research Centre; serving on the board of directors for J Douglas French Alzheimer's Foundation and Safely You; serving as medical advisor and receiving grant support from The Bluefield Project for Frontotemporal Dementia Research; consulting for Rainwater Charitable Foundation, Stanford Alzheimer's Disease Research Center, Buck Institute, Larry L. Hillblom Foundation, University of Texas Center for Brain Health, University of Washington Alzheimer's Disease Research Center, and Harvard University Alzheimer's Disease Research Center; receiving royalties from Guilford Press, Cambridge University Press, Johns Hopkins Press, and Oxford University Press; serving as editor for Neurocase; serving as section editor for Frontiers in Neurology; and receiving grants P30 AG062422, P01 AG019724, R01 AG057234, and T32 AG023481 from the NIH. Gil D. Rabinovici receives research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Genentech, Life Molecular Imaging. He has received consulting fees from Axon Neurosciences, Eisai, Genentech, GE Healthcare, Miller Medical Communications, Roche. He is an Associate Editor for JAMA Neurology. Howard J. Rosen reported consulting for Wave Neuroscience outside the submitted work. All other authors have no potential conflicts to disclose.
(© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)