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Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the \u201cwhole person\u201d genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P\u2009=\u20099.02\u2009\u00d7\u200910\u22127). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.<\/jats:p>","DOI":"10.1093\/hmg\/ddae067","type":"journal-article","created":{"date-parts":[[2024,4,28]],"date-time":"2024-04-28T23:43:47Z","timestamp":1714347827000},"page":"1315-1327","source":"Crossref","is-referenced-by-count":1,"title":["Association of whole-person eigen-polygenic risk scores with Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4413-1101","authenticated-orcid":false,"given":"Amin","family":"Kharaghani","sequence":"first","affiliation":[{"name":"Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health , 250 College Street, Toronto, ON M5T 1R8 , Canada"},{"name":"Dalla Lana School of Public Health, University of Toronto , 155 College Street, Toronto, ON M5T 3M7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Earvin S","family":"Tio","sequence":"additional","affiliation":[{"name":"Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health , 250 College Street, Toronto, ON M5T 1R8 , Canada"},{"name":"Institute of Medical Science , Department of Psychiatry, , 1 King's College Circle, Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto , Department of Psychiatry, , 1 King's College Circle, Toronto, ON M5S 1A8 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milos","family":"Milic","sequence":"additional","affiliation":[{"name":"Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health , 250 College Street, Toronto, ON M5T 1R8 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center , 1750 West Harrison Street, Chicago, IL 60612 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip L","family":"De Jager","sequence":"additional","affiliation":[{"name":"Centre for Translational and Computational Neuroimmunology, Columbia University Medical Center , 622 West 168th Street, New York, NY 10032 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A","family":"Schneider","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center , 1750 West Harrison Street, Chicago, IL 60612 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[{"name":"Dalla Lana School of Public Health, University of Toronto , 155 College Street, Toronto, ON M5T 3M7 , Canada"},{"name":"Department of Statistical Sciences, University of Toronto , 700 University Avenue, Toronto, ON M5G 1X6 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1831-9848","authenticated-orcid":false,"given":"Daniel","family":"Felsky","sequence":"additional","affiliation":[{"name":"Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health , 250 College Street, Toronto, ON M5T 1R8 , Canada"},{"name":"Dalla Lana School of Public Health, University of Toronto , 155 College Street, Toronto, ON M5T 3M7 , Canada"},{"name":"Institute of Medical Science , Department of Psychiatry, , 1 King's College Circle, Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto , Department of Psychiatry, , 1 King's College Circle, Toronto, ON M5S 1A8 , Canada"},{"name":"Department of Psychiatry, University of Toronto , 250 College Street, Toronto, ON M5T 1R8 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"key":"2024072221203551100_ref1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/alz.12328","article-title":"2021 Alzheimer\u2019s disease facts and figures","volume":"17","year":"2021","journal-title":"Alzheimers Dement"},{"key":"2024072221203551100_ref2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/s41593-020-0599-5","article-title":"The multiplex model of the genetics of Alzheimer\u2019s disease","volume":"23","author":"Sims","year":"2020","journal-title":"Nat Neurosci"},{"key":"2024072221203551100_ref3","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1001\/archpsyc.63.2.168","article-title":"Role of genes and environments for explaining Alzheimer disease","volume":"63","author":"Gatz","year":"2006","journal-title":"Arch Gen 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