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However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill\u2010defined. Here, we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from 44 individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag\u2010mass spectrometry. We demonstrate the utility of this resource in examining gene\u2010 and pathway\u2010level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC\u2010astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC\u2010derived astrocytes from individuals with AD are concordantly dysregulated in AD brain tissue. This includes increased levels of prefoldin proteins, extracellular matrix factors, COPI\u2010mediated trafficking components and reduced levels of proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC\u2010derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins in astrocytes. This study establishes an experimental system that integrates genetic information with a matched iPSC lines and brain tissue data from a large cohort of individuals to identify genetic contributions to molecular pathways affecting AD risk and resilience.<\/jats:p>","DOI":"10.1002\/glia.24677","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T02:09:41Z","timestamp":1738634981000},"page":"1166-1187","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Contributions of Genetic Variation in Astrocytes to Cell and Molecular Mechanisms of Risk and Resilience to Late\u2010Onset Alzheimer's Disease"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4741-0707","authenticated-orcid":false,"given":"Hyo","family":"Lee","sequence":"first","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Richard V.","family":"Pearse","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra M.","family":"Lish","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-1918","authenticated-orcid":false,"given":"Cheryl","family":"Pan","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham and Women's Hospital and Harvard Medical School  Boston 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Irving Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meichen","family":"Liao","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Center for Translational and Computational Neuroimmunology, Department of Neurology, and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain Columbia University Irving Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0521-779X","authenticated-orcid":false,"given":"Earvin S.","family":"Tio","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Institute of Medical Science University of Toronto  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