Alzheimer’s Disease Heterogeneity Explained by Polygenic Risk Scores Derived from Brain Transcriptomic Profiles

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 analysis and identified gene-sets (modules) which were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits for neuritic plaques (NPs) or neurofibrillary tangles (NFTs). We computed the module-based PRS (mbPRS) for each module and tested associations for mbPRSs with 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 as well as their matching AD-subgroups 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 to genetically-informed patient stratification and precision medicine in AD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the National Institute on Aging (NIA) grants, U01-AG068057, U19-AG068753, P30-AG072978, and RF1-AG057519. GWAS summary statistics used in this study were distributed by the National Institute on Aging Alzheimer Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01). Collection of study data provided by the Rush Alzheimer 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. Nilufer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer 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 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 Association; Alzheimer 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][1]). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer 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. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol, design, and performance of the current study were approved by the Boston University Institutional Review Board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes FHS data are available on the dbGaP (Study Accession ID: phs000056.v5.p3). ROSMAP resources can be requested at from the CommonMind Consortium portal (). Data used in preparation of this article were obtained from the Alzheimer Disease Neuroimaging Initiative (ADNI) database (). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: [http://adni.loni.usc.edu/wp-content/uploads/how\_to\_apply/ADNI\_Acknowledgement\_List.pdf][2]. [1]: http://www.fnih.org [2]: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf