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Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of\n                    <jats:italic>postmortem<\/jats:italic>\n                    AD tissue and APP\/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP\/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP\/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP\/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.\n                  <\/jats:p>","DOI":"10.1186\/s12974-026-03840-0","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T03:37:41Z","timestamp":1777865861000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"23","author":[{"given":"Ver\u00f3nica","family":"L\u00f3pez-L\u00f3pez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Iniesta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Gal\u00e1n-Ganga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Exp\u00f3sito-Coca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violeta","family":"Dur\u00e1n-Laforet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysha M.","family":"Bhojwani-Cabrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen M.","family":"Navarr\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Guillot-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose L.","family":"Venero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose V.","family":"S\u00e1nchez-Mut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Barco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Giralt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 P.","family":"L\u00f3pez-Atalaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"3840_CR1","doi-asserted-by":"publisher","unstructured":"2025 Alzheimer\u2019s disease facts and figures. 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