@article{c396c8cb18a74957b4a0b39005ee7694,
title = "Alzheimer's disease heterogeneity explained by polygenic risk scores derived from brain transcriptomic profiles",
abstract = "Introduction: Alzheimer's disease (AD) is heterogeneous, both clinically and neuropathologically. We investigated whether polygenic risk scores (PRSs) integrated with transcriptome profiles from AD brains can explain AD clinical heterogeneity. Methods: We conducted co-expression network analysis and identified gene sets (modules) that were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits including neuritic plaques (NPs) and neurofibrillary tangles (NFTs). We computed the module-based PRSs (mbPRSs) for each module and tested associations with mbPRSs for cognitive test scores, cognitively defined AD subgroups, and brain imaging data. Results: Of the modules significantly associated with NPs and/or NFTs, the mbPRSs from two modules (M6 and M9) showed distinct associations with language and visuospatial functioning, respectively. They matched clinical subtypes and brain atrophy at specific regions. Discussion: Our findings demonstrate that polygenic profiling based on co-expressed gene sets can explain heterogeneity in AD patients, enabling genetically informed patient stratification and precision medicine in AD. HIGHLIGHTS: Co-expression gene-network analysis in Alzheimer's disease (AD) brains identified gene sets (modules) associated with AD heterogeneity. AD-associated modules were selected when genes in each module were enriched for neuritic plaques and neurofibrillary tangles. Polygenic risk scores from two selected modules were linked to the matching cognitively defined AD subgroups (language and visuospatial subgroups). Polygenic risk scores from the two modules were associated with cognitive performance in language and visuospatial domains and the associations were confirmed in regional-specific brain atrophy data.",
keywords = "Alzheimer's disease, co-expression network, cognitive performance, genetic subtyping, module-based polygenic risk score, patient stratification, precision medicine",
author = "{Alzheimer's Disease Neuroimaging Initiative} and Jaeyoon Chung and Nathan Sahelijo and Toru Maruyama and Junming Hu and Rebecca Panitch and Weiming Xia and Jesse Mez and Stein, {Thor D.} and Saykin, {Andrew J.} and Haruko Takeyama and Farrer, {Lindsay A.} and Crane, {Paul K.} and Kwangsik Nho and Jun, {Gyungah R.}",
note = "Funding Information: This study was supported by the National Institute on Aging (NIA) grants, U01‐AG068057, U19‐AG068753, P30‐AG072978, RF1‐AG057519, and R56‐AG069130. GWAS summary statistics used in this study were distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24‐AG041689‐01). Collection of study data provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, was supported through funding by NIA grants P30‐AG10161, R01‐AG15819, R01‐AG17917, R01‐AG30146, R01‐AG36836, U01‐AG32984, U01‐AG46152, and U01‐AG61358, and funding from the Illinois Department of Public Health and the Translational Genomics Research Institute. Study data were also provided by Dr. Nil{\"u}fer Ertekin‐Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL, using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Collection of these data was supported through funding by NIH grants P50‐AG016574, R01‐AG032990, U01‐AG046139, R01‐AG018023, U01‐AG006576, U01‐AG006786, R01‐AG025711, R01‐AG017216, R01‐AG003949, and R01‐NS080820, and by funding from the CurePSP Foundation and the Mayo Foundation. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Publisher Copyright: {\textcopyright} 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
year = "2023",
doi = "10.1002/alz.13069",
language = "English (US)",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier",
}