Exercise and the Neurovascular Unit in Alzheimer’s Disease: Modulating Aβ Disposition Across Brain-to-Blood, Perivascular, and Vessel-Wall Pathways

Cerebral amyloid-β (Aβ) burden in Alzheimer’s disease (AD) reflects the balance among peptide production, degradation, movement between compartments and retention within cerebral vessel walls. Across the reviewed evidence, cerebrovascular adaptation was the most consistently observed exercise response, although its direction and measurement varied across studies and it did not by itself establish Aβ removal. Direct evidence for exercise-related Aβ movement was narrower and predominantly preclinical. Animal studies report improved vascular responsiveness, blood–brain barrier-related phenotypes and aquaporin-4-sensitive fluid exchange; selected tracer experiments further show greater short-term recovery of brain-administered Aβ in blood, lymphatic or peripheral compartments. Cellular and peripheral studies identify candidate routes for the degradation and downstream handling of redistributed peptide. Human trials generally show improved fitness or cerebrovascular function without clear between-group changes in Aβ-PET or plasma Aβ over the measured periods. The pattern is compartment- and timescale-specific: functional adaptation and measured amyloid burden capture different components of the exercise response. Source-matched recovery in a downstream compartment, when coupled with a time-resolved decline in the same brain-derived signal, can establish net removal from the brain but not whole-body terminal disposal; the latter requires verified irreversible degradation or excretion of the tracked peptide. The sustained net removal of endogenous brain Aβ also requires a concurrent assessment of production and vessel-wall retention. Overall, cerebrovascular and fluid-transport adaptation is the best-supported exercise-responsive context for Aβ disposition, whereas neither sustained net removal of brain Aβ nor whole-body terminal disposal has been established in human exercise studies.