The spleen-brain axis in Alzheimer's disease and related dementias: Integrating immune and metabolic regulation.

Emerging evidence highlights the central role of peripheral immune-metabolic regulation in the pathogenesis of Alzheimer's disease and related dementias (ADRD). Among peripheral organs, the spleen has gained increasing attention as a critical immune-metabolic hub linking systemic homeostasis to central neurodegeneration. This review systematically elucidates the regulatory functions of the spleen-brain axis from three complementary perspectives: (1) structural remodeling and immunopathological alterations of the spleen in ADRD; (2) spleen-driven 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-metabolic crosstalk, such as Toll-like receptor 4 (TLR4)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NLR family pyrin domain containing 3 (NLRP3) inflammasome, high-mobility group box 1 (HMGB1)-receptor for advanced glycation end-products (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-metabolic regulator, highlights spleen-targeted interventions as a potential therapeutic strategy for ADRD.