Exercise-conditioned extracellular vesicles in Alzheimer's disease: a multi-organ signaling network linking peripheral adaptation to brain pathology.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which amyloid-β accumulation, tau pathology, chronic neuroinflammation, cerebrovascular impairment, and synaptic dysfunction act as interconnected rather than independent processes. Physical exercise is protective against several of these features, but how its peripheral effects produce coordinated changes in the brain remains only partly defined. Soluble exerkines explain part of this benefit, but they act individually, do not protect labile cargo such as RNA, and carry little information about their cell of origin. Extracellular vesicles (EVs) offer a complementary mechanism. By packaging diverse cargo within a membrane, they co-deliver several signals at once, protect labile cargo in transit, and carry a profile that partly reflects the state and origin of the releasing cell. In this review, we develop a multi-organ signaling framework in which exercise-conditioned EVs link peripheral exercise adaptation to AD-related brain pathology. We examine how exercise reshapes EV biogenesis, the circulating EV pool, and EV engagement with the neurovascular interface. We then map how exercise-conditioned EVs intersect with amyloid aggregation and clearance, tau propagation, neuroinflammation, blood-brain barrier integrity, and synaptic and neurogenic resilience, and which tissues contribute to the exercise-responsive EV pool. Several bottlenecks keep the field at the level of association rather than causation, including cargo heterogeneity, uncertain tissue-of-origin attribution, and the gap between describing cargo and demonstrating its function. This framework outlines a realistic, staged route from current associative evidence toward clinical application, in which exercise-conditioned EVs serve first as biomarkers of exercise responsiveness and later as engineered therapeutic platforms for AD.