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Here we introduce an analysis framework, namely MD-AD (Multi-task Deep learning for Alzheimer\u2019s Disease neuropathology), which leverages an unexpected synergy between DNNs and multi-cohort settings. In these settings, true joint analysis can be stymied using conventional statistical methods, which require \u201charmonized\u201d phenotypes and tend to capture cohort-level variations, obscuring subtler true disease signals. Instead, MD-AD incorporates related phenotypes sparsely measured across cohorts, and learns interactions between genes and phenotypes not discovered using linear models, identifying subtler signals than cohort-level variations which can be uniquely recapitulated in animal models and across tissues. We show that MD-AD exploits sex-specific relationships between microglial immune response and neuropathology, providing a nuanced context for the association between inflammatory genes and Alzheimer\u2019s Disease.<\/jats:p>","DOI":"10.1038\/s41467-021-25680-7","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T06:03:22Z","timestamp":1631253802000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Unified AI framework to uncover deep interrelationships between gene expression and Alzheimer\u2019s disease neuropathologies"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7031-2665","authenticated-orcid":false,"given":"Nicasia","family":"Beebe-Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safiye","family":"Celik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Weinberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Sturmfels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mostafavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5833-5215","authenticated-orcid":false,"given":"Su-In","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,10]]},"reference":[{"key":"25680_CR1","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1038\/s41593-018-0240-z","volume":"21","author":"PL De Jager","year":"2018","unstructured":"De Jager, P. 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