Dysfunction of the glymphatic system has been proposed as a mechanistic link between sleep disruption and Alzheimer's disease (AD). In animal models, glymphatic impairment alone can drive AD pathology. Whether this system clears amyloid beta (Aβ) and tau in humans remains unknown. In a randomized crossover trial with 39 participants, we found that glymphatic clearance during normal sleep increased morning plasma levels of AD biomarkers compared to sleep deprivation. Participants underwent overnight monitoring using an investigational device that measured dynamic changes in synaptic-metabolic release and glymphatic activity. The observed changes mirrored predictions from a multicompartment model based on published data on Aβ and tau release and clearance. Our findings indicate that sleep-active physiological processes, particularly reduced brain parenchymal resistance, enhance overnight glymphatic clearance of AD biomarkers to plasma. These results support a key role for glymphatic function in AD pathophysiology and suggest its enhancement as a potential therapeutic strategy to slow disease progression.
© 2026. The Author(s).