Extracellular vesicle-mediated bidirectional communication between the brain and peripheral organs in Alzheimer’s disease: evidence, mechanisms, and translational perspectives

Alzheimer's disease (AD) has traditionally been conceptualized as a brain-centered neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, and progressive neuronal loss. However, accumulating evidence suggests that AD is also shaped by systemic disturbances and reciprocal communication between the central nervous system and peripheral organs. Extracellular vesicles (EVs), which transport proteins, lipids, metabolites, and nucleic acids across biological fluids and barriers, have emerged as plausible mediators of this inter-organ crosstalk. In this Review, current evidence for EV-mediated bidirectional communication between the brain and peripheral organs is synthesized, with particular attention to the liver-brain, heart-brain, gut-brain, lung-brain, bone-brain, and adipose-brain axes. The strength of evidence across these axes is compared, and the ways in which organ-derived EVs may influence neuroinflammation, neurovascular dysfunction, metabolic homeostasis, blood-brain barrier integrity, and Aβ/tau-related processes are discussed, while also considering how brain-derived EVs (BDEVs) may affect peripheral physiology. The translational potential of EVs as diagnostic biomarkers, therapeutic carriers, and candidate targets for systemic intervention in AD is further evaluated. Current evidence most strongly supports the gut-brain, liver-brain, and adipose-brain axes, whereas several other axes remain supported primarily by experimental models or engineered EV studies. Major barriers to progress include EV heterogeneity, limited source specificity, insufficient standardization of isolation and quantification workflows, and a continuing reliance on associative human data and preclinical models. Overall, EVs are best viewed as one candidate signaling layer within a broader systemic network linking peripheral physiology to brain pathology. Clarifying the magnitude, directionality, and causal significance of these interactions will require rigorous EV characterization, source-resolved in vivo trafficking studies, and longitudinal clinical investigation.