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We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example,\n                    <jats:italic>APOE<\/jats:italic>\n                    ,\n                    <jats:italic>ACTB<\/jats:italic>\n                    ,\n                    <jats:italic>IL6<\/jats:italic>\n                    and\n                    <jats:italic>INS<\/jats:italic>\n                    ). Genetic colocalization analysis supports AD association with hyperlipidemia at the\n                    <jats:italic>APOE<\/jats:italic>\n                    locus, as well as a stronger female AD association with osteoporosis at a locus near\n                    <jats:italic>MS4A6A<\/jats:italic>\n                    . We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.\n                  <\/jats:p>","DOI":"10.1038\/s43587-024-00573-8","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T06:03:07Z","timestamp":1708495387000},"page":"379-395","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Leveraging electronic health records and knowledge networks for Alzheimer\u2019s disease prediction and sex-specific biological insights"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4745-0714","authenticated-orcid":false,"given":"Alice S.","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine P.","family":"Rankin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Cerono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Miramontes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunter","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1823-0421","authenticated-orcid":false,"given":"Jacquelyn","family":"Roger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billy","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Soman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1873-8575","authenticated-orcid":false,"given":"Sarah","family":"Woldemariam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2034-8800","authenticated-orcid":false,"given":"Riley","family":"Bove","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Glymour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6117-8764","authenticated-orcid":false,"given":"Nima","family":"Aghaeepour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7393-5120","authenticated-orcid":false,"given":"Tomiko T.","family":"Oskotsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel E.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan J.","family":"Sanders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0067-194X","authenticated-orcid":false,"given":"Sergio","family":"Baranzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-6083","authenticated-orcid":false,"given":"Marina","family":"Sirota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"573_CR1","doi-asserted-by":"crossref","unstructured":"2022 Alzheimer\u2019s disease facts and figures. 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Also unrelated to the work, K.P.R. has served on a medical advisory board for Eli Lily. S.B. is co-founder of Mate Bioservices. J.R. has previously interned at Roche. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}