Glymphatic Dysfunction in Alzheimer’s Disease: Mechanisms,Biomarkers, and Emerging Therapeutic Perspectives

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, with hallmark pathological features including amyloid-beta plaques, tau tangles, and neuronal loss. The glymphatic system, a recently discovered network responsible for brain waste clearance, plays a crucial role in maintaining cerebral homeostasis by facilitating the removal of neurotoxic metabolites, including amyloid-beta. Disruption of glymphatic function has emerged as a key factor in AD pathophysiology, contributing to the accumulation of toxic proteins and accelerating neurodegenerative processes. This narrative review explores the complex interplay between glymphatic dysfunction and AD. We discuss the mechanisms of the glymphatic system, emphasizing its reliance on cerebrospinal fluid (CSF) and interstitial fluid flow to clear metabolic waste, and how this process is closely linked to sleep cycles. In AD, impaired glymphatic function, exacerbated by aging and sleep disturbances, accelerates the buildup of amyloid-beta and tau, driving neurodegeneration. Furthermore, sleep disturbances commonly observed in AD patients further hinder glymphatic activity, creating a vicious cycle that exacerbates cognitive decline. Emerging therapeutic approaches aimed at enhancing glymphatic function—including sleep regulation, pharmacological agents, and lifestyle interventions—are promising, but most findings remain preliminary and largely based on animal studies or early clinical observations. These strategies should therefore be considered exploratory until validated in large-scale human trials. By restoring efficient waste clearance, such interventions may offer novel avenues for slowing or preventing AD progression.