Glymphatic dysfunction in neurodegeneration: From impaired clearance to mechanism-driven therapeutic innovation

Glymphatic system refers to a system that involves perivascular clearance mechanisms within the brain, which are crucial for the elimination of neurotoxic proteins such as amyloid-β (Aβ) and tau proteins in Alzheimer's disease (AD), α-synuclein in Parkinson's disease (PD), and mutant huntingtin (mHTT) in Huntington's disease (HD). There is mounting evidence suggesting that glymphatic dysfunction is an important cause of neurodegenerative diseases, characterized by failure of cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange due to abnormal clearance. Mechanistically, this dysfunction is affected by aging, astroglial aquaporin-4 (AQP4) depolarization, vascular impairment, sleep abnormalities, oxidative damage, and neuroinflammation. Additionally, aberrant glymphatic flow acts as a crucial link between peripheral and central pathologies, amplifying neurodegeneration via altered solute transport and inflammation signaling. Glymphatic dysfunction has been found to be involved in diseases such as AD, PD and HD, thus indicating the widespread significance of glymphatic pathology. Therapeutically, targeting glymphatic function through modulation of AQP4 polarization, improving sleep-dependent clearance, and decreasing oxidative and inflammatory mechanisms may provide promising strategy for disease modification. This review provides a comparative and mechanistic overview of glymphatic dysfunction across AD, PD, and HD, highlighting peripheral-central interactions, biomarkers, imaging approaches, and therapeutic strategies, while addressing unresolved issues related to transport mechanisms, causality versus epiphenomenon, and translational limitations.