Physical exercise as a non-pharmacological strategy to enhance glymphatic function

The glymphatic system plays a critical role in clearing metabolic waste and neurotoxic proteins from the brain, and its dysfunction is implicated in neurodegenerative diseases such as Alzheimer's disease (AD). Emerging evidence indicates that physical exercise enhances glymphatic function through multiple mechanisms, including increased cerebrospinal fluid (CSF) influx, improved perivascular clearance, astrocytic aquaporin-4 (AQP4) polarization, and modulation of vascular and sleep-dependent processes. Preclinical studies demonstrated that voluntary wheel running and aerobic exercise reduce amyloid-β (Aβ) accumulation, attenuate neuroinflammation, and improve cognitive performance in both aging and AD mouse models, with benefits being highly dependent on AQP4 expression and the timing of intervention. Translational evidence in humans showed that structured aerobic and multicomponent exercise increases glymphatic and meningeal lymphatic activity, enhances vascular dynamics, reduces systemic inflammation, and improves sleep quality, leading to measurable cognitive gains. Despite these promising findings, methodological challenges-such as limitations of non-invasive imaging, difficulty establishing causality, and reliance on short-term interventions-highlight the need for longitudinal, multimodal studies that integrate imaging, cardiovascular, sleep, and cognitive metrics. Collectively, these data suggest that exercise represents a potent non-pharmacological strategy to augment glymphatic clearance, preserve neural homeostasis, and reduce the risk of cognitive decline. This review will summarize evidence on exercise-induced glymphatic enhancement, highlight mechanisms, and identify research gaps for future studies on brain health.