Impaired glymphatic clearance as a mechanistic link between brain aging and neurodegenerative disease pathogenesis

The perivascular glymphatic system promotes cerebrospinal fluid-interstitial fluid (CSF-ISF) interaction and macromolecular waste clearance and is an important determinant of brain homeostasis, the performance of which deteriorates with age. Astrocyte biology, vascular integrity, and age-associated cerebrovascular dynamic alterations interfere with the polarization of aquaporin-4 (AQP4) water channels on astrocytic endfeet, decreasing the clearance of aggregation-prone proteins, such as amyloid-β, tau, and α-synuclein. Experimental research indicates that aging is associated with a decrease in cerebrospinal fluid influx and solute clearance efficiency, and human neuroimaging research indicates progressive age-related dysfunction of glymphatic transport, which is associated with pathological protein accumulation and cognitive impairment. Glymphatic dysfunction is mechanistically associated with clearance failure and disease progression in Alzheimer 's and Parkinson's diseases and is also observed in other age-related diseases, such as cerebral small vessel disease, traumatic brain injury, and neuroinflammatory disease. Emerging evidence suggests that glymphatic efficiency can be restored by intervening in some of the underlying aging processes, including sleep regulation, cardiovascular health, astrocyte-vascular coupling, and pharmacological manipulation of AQP4 polarisation. This review places glymphatic dysfunction as a fundamental, potentially alterable outcome of brain aging with the implication of preventing neurodegenerative diseases and supporting healthy cognitive aging.