{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T13:34:47Z","timestamp":1787924087351,"version":"build-2784847793"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Immunometabolic dysregulation orchestrating bidirectional peripheral\u2013central inflammatory crosstalk has been increasingly recognized as a contributor to Alzheimer\u2019s disease (AD) pathogenesis, challenging the conventional view of AD as an isolated central disorder dominated by amyloid-beta (A\u03b2) and tau pathology. However, although central immune-metabolic disturbances are well established, this perspective largely overlooks peripherally derived regulatory signals from systemic circulation. Classical peripheral-to-central pathways, such as immune cell infiltration and cytokine leakage, depend on overt blood\u2013brain barrier (BBB) damage and cannot account for the latent neuroinflammation characteristic of the prodromal stage, when neurovascular units remain largely intact. To address this gap, we review recent advances on circulating soluble metabolites (&amp;lt;500 Da)\u2014key immunometabolic mediators linking systemic disturbances to central lesions\u2014and organize them into three groups by biosynthetic origin (a heuristic, non-taxonomic classification): peripheral immune-derived, gut microbiota-derived, and systemic host metabolic intermediates. We outline the transmembrane transport shifts associated with progressive BBB dysfunction and the downstream intracellular cascades\u2014such as mitochondrial redox disturbance, mTOR\u2013NLRP3 inflammasome activation, and histone epigenetic remodeling\u2014that mediate this crosstalk. Importantly, although these proposed associations are mechanistically informative, they remain largely unsupported by direct human evidence and require further validation in large AD cohorts; nevertheless, several individual metabolite biomarkers already show consistent clinical association. This framework clarifies the multi-stage immunometabolic axis and may inform the development of ultra-early fluid biomarkers and peripheral-targeted immunometabolic interventions.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1939482","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T13:12:49Z","timestamp":1787922769000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral-central inflammatory crosstalk in Alzheimer\u2019s disease: immunometabolic functions of circulating soluble metabolites under dynamic blood-brain barrier states"],"prefix":"10.3389","volume":"17","author":[{"given":"Nannan","family":"Song","sequence":"first","affiliation":[{"name":"Jiangxi University of Chinese Medicine (JXUCM)","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Xing","sequence":"additional","affiliation":[{"name":"Jiangxi University of 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