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Among peripheral organs, the spleen has gained increasing attention as a critical immune\u2013metabolic hub linking systemic homeostasis to central neurodegeneration. This review systematically elucidates the regulatory functions of the spleen\u2013brain axis from three complementary perspectives: (1) structural remodeling and immunopathological alterations of the spleen in ADRD; (2) spleen\u2010driven immunometabolic crosstalk, which integrates immune function with iron homeostasis, glucolipid metabolism, and amino acid turnover, contributing to the progression of neurodegenerative pathology; and (3) key molecular pathways mediating immune\u2013metabolic crosstalk, such as Toll\u2010like receptor 4 (TLR4)\u2013nuclear factor kappa\u2010light\u2010chain\u2010enhancer of activated B cells (NF\u2010\u03baB), NLR family pyrin domain containing 3 (NLRP3) inflammasome, high\u2010mobility group box 1 (HMGB1)\u2013receptor for advanced glycation end\u2010products (RAGE), and Janus kinase\/signal transducer and activator of transcription protein (JAK\/STAT) signaling. We systematically elucidate how splenic dysfunction drives a positive feedback loop involving systemic inflammation, metabolic disorder, and neuroinflammation. This novel perspective, which views the spleen as an integrated immune\u2013metabolic regulator, highlights spleen\u2010targeted interventions as a potential therapeutic strategy for ADRD.<\/jats:p>","DOI":"10.1002\/alz.71243","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:01:45Z","timestamp":1773010905000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The spleen\u2013brain axis in Alzheimer's disease and related dementias: Integrating immune and metabolic regulation"],"prefix":"10.1002","volume":"22","author":[{"given":"Jingsi","family":"Yan","sequence":"first","affiliation":[{"name":"Science and Technology Innovation Center Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Science and Technology Innovation Center Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Ye","sequence":"additional","affiliation":[{"name":"Science and Technology Innovation Center Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Science and Technology Innovation Center Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Li","sequence":"additional","affiliation":[{"name":"Central Lab Shenzhen Bao'an Chinese Medicine Hospital Guangzhou University of Chinese Medicine  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weirong","family":"Li","sequence":"additional","affiliation":[{"name":"Science and Technology Innovation Center Guangzhou University of Chinese Medicine  Guangzhou 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