@article{0b545f0bb0584f54b189d90ba43d7324,
title = "Multilocus genetic profiling to empower drug trials and predict brain atrophy",
abstract = "Designers of clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) are actively considering structural and functional neuroimaging, cerebrospinal fluid and genetic biomarkers to reduce the sample sizes needed to detect therapeutic effects. Genetic pre-selection, however, has been limited to Apolipoprotein E (ApoE). Recently discovered polymorphisms in the CLU, CR1 and PICALM genes are also moderate risk factors for AD; each affects lifetime AD risk by \textasciitilde{} 10-20\%. Here, we tested the hypothesis that pre-selecting subjects based on these variants along with ApoE genotype would further boost clinical trial power, relative to considering ApoE alone, using an MRI-derived 2-year atrophy rate as our outcome measure. We ranked subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on their cumulative risk from these four genes. We obtained sample size estimates in cohorts enriched in subjects with greater aggregate genetic risk. Enriching for additional genetic biomarkers reduced the required sample sizes by up to 50\%, for MCI trials. Thus, AD drug trial enrichment with multiple genotypes may have potential implications for the timeliness, cost, and power of trials.",
keywords = "Alzheimer's disease, Brain atrophy, Clinical trial enrichment, Genetic risk score, Genetics, Neuroimaging",
author = "Omid Kohannim and Xue Hua and Priya Rajagopalan and Hibar, \{Derrek P.\} and Neda Jahanshad and Grill, \{Joshua D.\} and Apostolova, \{Liana G.\} and Toga, \{Arthur W.\} and Jack, \{Clifford R.\} and Weiner, \{Michael W.\} and Thompson, \{Paul M.\}",
note = "Funding Information: Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904 ). ADNI is funded by the National Institute on Aging , and the National Institute of Biomedical Imaging and Bioengineering , and through generous contributions from the following: Abbott ; Alzheimer's Association ; Alzheimer's Drug Discovery Foundation ; Amorfix Life Sciences Ltd. ; AstraZeneca ; Bayer HealthCare ; BioClinica, Inc. ; Biogen Idec Inc. ; Bristol-Myers Squibb Company ; Eisai Inc. ; Elan Pharmaceuticals Inc. ; Eli Lilly and Company ; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc. ; GE Healthcare ; Innogenetics, N.V. ; Janssen Alzheimer Immunotherapy Research \& Development, LLC. ; Johnson \& Johnson Pharmaceutical Research \& Development LLC. ; Medpace, Inc. ; Merck \& Co., Inc. ; Meso Scale Diagnostics, LLC. ; Novartis Pharmaceuticals Corporation ; Pfizer Inc. ; Servier ; Synarc Inc. ; and Takeda Pharmaceutical Company . The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514 . Algorithm development and image analysis for this study was funded by grants to P.T. from the NIBIB ( R01 EB007813 , R01 EB008281 , and R01 EB008432 ), NICHD ( R01 HD050735 ), and NIA ( R01 AG020098 ). O.K. was supported by NIH F30 AG041681 and the UCLA Dissertation Year Fellowship . D.H. is partially supported by NSF GRFP Grant DGE-0707424 . N.J. was additionally supported by NIH NLM Grant T15 LM07356 . Funding Information: The authors have no financial disclosures and declare no competing financial interests, but some have received commercial funding unrelated to the topic of the paper. M. Weiner is on the following scientific advisory boards: Lilly, Araclon and Institut Catala de Neurociencies Aplicades, Gulf War Veterans Illnesses Advisory Committee, VACO, Biogen Idec, and Pfizer; received funding for consulting from: Astra Zeneca, Araclon, Medivation/Pfizer, Ipsen, TauRx Therapeutics LTD, Bayer HealthCare, Biogen Idec, Exonhit Therapeutics, SA, Servier, Synarc, Pfizer, and Janssen; received funding for travel from: NeuroVigil, Inc., CHRU-Hopital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Lilly, University of California, San Diego-ADNI, Paris University, Institut Catala de Neurociencies Aplicades, University of New Mexico School of Medicine, Ipsen, CTAD (Clinical Trials on Alzheimer's Disease), Pfizer, AD PD Meeting, Paul Sabatier University, Novartis, and Tohoku University; received honoraria from: PMDA /Japanese Ministry of Health, Labour, and Welfare, Tohoku University, Neuro Vigil, Inc., and Insitut Catala de Neurociencies Aplicades; and received research support from: Merck, Avid , DoD , VA ; Stock Options: Synarc, Elan ; organizations contributing to the Foundation for NIH and thus to the NIA funded Alzheimer's Disease Neuroimaging Initiative: Abbott, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Anonymous Foundation , AstraZeneca, Bayer HealthCare, BioClinica, Inc. (ADNI 2), Bristol-Myers Squibb, Cure Alzheimer's Fund , Eisai, Elan, Gene Network Sciences , Genentech, GE Healthcare, GlaxoSmithKline , Innogenetics, Johnson \& Johnson, Eli Lilly \& Company, Medpace, Merck, Novartis, Pfizer Inc., Roche, Schering Plough , Synarc, and Wyeth . ",
year = "2013",
doi = "10.1016/j.nicl.2013.05.007",
language = "English",
volume = "2",
pages = "827--835",
journal = "NeuroImage: Clinical",
issn = "2213-1582",
publisher = "Elsevier Inc.",
number = "1",
}