The Role of the Glymphatic System in Alzheimer's Disease: Mechanisms, Evidence, and Therapeutic Implications.

Abstract

Alzheimer's disease (AD) is an aging-associated neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation and progressive cognitive decline. Increasing evidence implicates the glymphatic system, a brain-wide perivascular pathway involved in cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, in the removal of Aβ, tau, and other solutes relevant to AD pathogenesis. Aging-related alterations in aquaporin-4 polarization, arterial pulsatility, sleep architecture, and cerebrovascular integrity may impair glymphatic transport and thereby promote protein retention and neurodegeneration. In this review, we summarize current knowledge of glymphatic anatomy and function and discuss its implications for AD, with particular emphasis on modifiable factors such as sleep, exercise, vascular health, and aging-associated decline. We further highlight emerging therapeutic and potential intervention strategies aimed at restoring glymphatic function, and critically evaluate current methods for assessing this system in humans together with the evidence obtained to date. Although human studies increasingly support the relevance of perivascular fluid transport to AD-related pathology and cognitive outcomes, mechanistic insights remain largely derived from animal models, and human assessment is still constrained by methodological and imaging limitations. Overall, the glymphatic system provides a useful framework for linking brain aging to impaired clearance in AD. Further refinement of human biomarkers and longitudinal translational studies will be essential for clarifying their clinical relevance and therapeutic potential.