Glymphatic dysfunction and amyloid-β clearance in Alzheimer’s disease: mechanistic insights and therapeutic potential of traditional Chinese medicine

The glymphatic system supports cerebrospinal fluid–interstitial fluid (CSF–ISF) exchange and extracellular solute transport, and its dysfunction may contribute to amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD). This narrative review examines mechanisms linking impaired brain fluid transport to Aβ retention, focusing on altered perivascular aquaporin-4 (AQP4) polarization, vascular and paravascular remodeling, impaired cerebrovascular dynamics, astrocyte dysfunction, neuroinflammation, and sleep and circadian disturbances. It also evaluates preclinical evidence for Chinese herbal interventions. Preclinical studies have reported changes in CSF tracer influx or distribution, parenchymal solute efflux, meningeal lymphatic tracer transport, AQP4 localization, and lymphatic vessel morphology, often accompanied by reduced Aβ burden and improved cognitive performance. Other studies primarily report changes in cellular Aβ handling, inflammation, or sleep and therefore provide only indirect support for glymphatic involvement. Glymphatic exchange, intramural periarterial drainage, and meningeal lymphatic outflow are anatomically distinct processes with different experimental readouts; reduced tissue Aβ alone does not establish enhanced clearance. Major limitations include heterogeneity in experimental models and tracer methods, limited pathway-specific causal validation, and a lack of clinical evidence directly supporting these mechanisms of action. Dynamic transport measurements, pathway-specific perturbations, and standardized formulations are needed to determine whether enhancement of brain fluid and solute clearance represents a clinically translatable mechanism of Chinese herbal interventions in AD.