Glymphatic Impairment in Neurodegeneration: A Narrative Review of Pathogenesis and Biomarker Trajectories

Abstract

The glymphatic system has emerged as an important pathway for maintaining central nervous system (CNS) homeostasis by facilitating the clearance of interstitial solutes, including neurotoxic proteins such as amyloid-β, tau, and α-synuclein. It functions through perivascular channels supported by astrocytic aquaporin-4 (AQP4) water channels. This system enables cerebrospinal fluid (CSF) influx and interstitial fluid (ISF) efflux across the brain parenchyma. Increasing evidence indicates that dysfunction of the glymphatic system plays a critical role in the early pathogenesis and progression of several neurodegenerative diseases. This narrative review synthesizes recent human-based studies published between 2020 and 2025, focusing on glymphatic dysfunction in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and behavioral variant frontotemporal dementia. Findings suggest that impaired clearance of neurotoxic proteins due to AQP4 depolarization, loss of perivascular localization, and disruption of CSF-ISF (Cerebrospinal Fluid- Interstitial Fluid) dynamics contributes to protein aggregation, neuroinflammation, and cognitive decline. The review also highlights how changes in sleep architecture, cardiovascular health, and environmental exposures may influence glymphatic activity. Furthermore, it explores the growing significance of imaging techniques such as diffusion tensor imaging along perivascular spaces (DTI-ALPS) and the measurement of CSF biomarkers like AQP4 and neurofilament light, which may serve as early indicators of glymphatic dysfunction and disease progression. Particular attention is given to the interplay between choroid plexus enlargement, inflammation, and glymphatic disruption in multiple sclerosis, as well as compensatory glymphatic responses observed in early neurodegeneration. These insights suggest that assessing glymphatic function could enhance diagnostic accuracy, allow for earlier intervention, and inform the development of targeted therapies. While the field is still evolving, and limitations exist in current imaging and biomarker specificity, the glymphatic system holds promise not only as a window into the underlying mechanisms of neurodegeneration but also as a potential therapeutic target. This review aims to bridge the gap between emerging mechanistic understanding and clinical translation, providing a framework for future research into glymphatic-based diagnostics and interventions.