Glymphatic Function in Health and Neurological Disease: Mechanisms and Emerging Therapeutic Targets

Abstract

Background: The glymphatic system is a recently characterized brain-wide transport pathway that supports the movement of cerebrospinal fluid through perivascular spaces, enabling removal of metabolic waste and potentially harmful proteins from neural tissue. Efficient functioning of this clearance mechanism is essential for maintaining neuronal stability and cognitive performance. Disturbances in glymphatic activity have been increasingly linked with neurological disorders. Although substantial progress has been made, the precise mechanisms governing glymphatic transport particularly the relative contributions of diffusion and bulk flow remain under active scientific debate. Objective: The present review aims to provide a comprehensive overview of the structure and physiological mechanisms of the glymphatic system, its regulatory factors, its contribution to neurological disease development, and potential therapeutic strategies targeting its function. Mechanisms and Pathophysiological Implications: The glymphatic pathway operates through coordinated cerebrospinal fluid influx along periarterial spaces and interstitial fluid clearance via perivenous routes, largely mediated by aquaporin-4 channels located on astrocytic endfeet. Physiological factors such as sleep patterns, vascular pulsations, body posture, autonomic signaling, and aging significantly influence system efficiency. Impairment of glymphatic clearance contributes to accumulation of neurotoxic proteins, including amyloid and tau, which are associated with neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and idiopathic normal pressure hydrocephalus. Recent advances in imaging modalities and computational approaches have enhanced understanding of glymphatic dynamics and highlighted its therapeutic relevance. Conclusion: The glymphatic system represents a promising target for preventive and therapeutic strategies in neurological diseases. Translating emerging experimental insights into effective clinical interventions remains a critical priority for future research.