Sleep-Dependent Clearance of Brain Metabolites via the Glymphatic System: Implications for Alzheimer's Pathophysiology.

PURPOSE: This review aims to examine how sleep-dependent glymphatic function contributes to the clearance of brain metabolites involved in Alzheimer's disease (AD), with particular emphasis on amyloid-beta (Aβ), tau, astrocytic aquaporin-4 (AQP4), and emerging biomarkers of clearance-related dysfunction. METHOD: A narrative review of recent mechanistic, preclinical, and human studies was conducted to synthesize current evidence linking sleep, glymphatic transport, and AD pathophysiology. Findings from animal experiments, diffusion MRI proxies such as diffusion tensor imaging analysis along the perivascular space (DTI-ALPS), biomarker studies, and translational intervention research were integrated, with attention to sleep physiology, vascular dynamics, and neuromodulatory regulation. FINDINGS: Available evidence indicates that sleep is an active physiological state that facilitates cerebrospinal fluid (CSF) exchange with interstitial fluid and promotes the removal of neurotoxic solutes from the brain. Glymphatic transport appears to be most active during non-rapid eye movement sleep, particularly during slow-wave activity, when interstitial space expands and CSF-interstitial fluid exchange increases. Experimental studies show that sleep enhances the clearance of Aβ, tau, and related metabolites, whereas sleep disruption, aging, vascular dysfunction, and AQP4 abnormalities impair this process and may accelerate AD-related pathology. Human evidence has also advanced, including DTI-ALPS studies and a 2026 randomized crossover study reporting higher morning plasma amyloid and tau levels after normal sleep than after sleep deprivation, consistent with greater overnight brain-to-blood clearance during sleep. CONCLUSION: Sleep-dependent glymphatic clearance is increasingly recognized as an important component of brain homeostasis and a plausible contributor to AD pathophysiology, with promising implications for biomarker development, prevention, and future therapeutic translation.