Peripheral-central inflammatory crosstalk in Alzheimer's disease: immunometabolic functions of circulating soluble metabolites under dynamic blood-brain barrier states.

Immunometabolic dysregulation orchestrating bidirectional peripheral-central inflammatory crosstalk has been increasingly recognized as a contributor to Alzheimer's disease (AD) pathogenesis, challenging the conventional view of AD as an isolated central disorder dominated by amyloid-beta (Aβ) 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-brain 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 (<500 Da)-key immunometabolic mediators linking systemic disturbances to central lesions-and 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-such as mitochondrial redox disturbance, mTOR-NLRP3 inflammasome activation, and histone epigenetic remodeling-that 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.