Exercise-induced modulation of astrocyte in Alzheimer's disease: mechanisms and therapeutic implications.

Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, tau pathology, and chronic neuroinflammatory responses, although the relative contribution of these processes varies across disease stage and patient population. Current pharmacological therapies provide limited symptomatic benefit or modest disease-slowing effects in selected populations, underscoring the need for safe and sustainable adjunctive interventions. Astrocytes are central regulators of synaptic homeostasis, metabolic support, vascular coupling, and perivascular solute clearance, and these functions are profoundly altered in AD. For heuristic purposes, reactive astrocytes are often described along an A1-like to A2-like spectrum, with the former associated with pro-inflammatory and neurotoxic programs and the latter with reparative and neurotrophic functions; however, emerging single-cell and spatial transcriptomic data indicate that astrocyte states in AD are heterogeneous and context dependent rather than strictly binary. Growing evidence, predominantly from preclinical studies, suggests that exercise may remodel astrocyte-associated inflammatory, metabolic, and clearance pathways, with potential benefits for AD-related pathology and cognition. In several rodent models, exercise has been associated with reduced expression of A1-like reactive markers, enhanced protective astrocyte-associated programs, improved astrocyte-neuron metabolic coupling, and better perivascular localization of aquaporin-4 (AQP4). These changes may contribute to reduced inflammatory signaling and more efficient clearance of Aβ and tau, although the extent to which AQP4-dependent perivascular clearance mechanisms mediate exercise benefits in humans remains uncertain. Here, we review current evidence on how exercise influences astrocyte biology in AD, distinguish preclinical from clinical findings, and discuss key translational modifiers-including exercise modality, disease stage, sex, and APOE genotype-to inform glia-aware therapeutic strategies and future exercise prescriptions.