The glymphatic system clears amyloid beta and tau from brain to plasma in humans

ABSTRACT Poor sleep is implicated in the development of Alzheimer’s disease (AD) pathology and cognitive impairment. Dysfunction of the glymphatic system has been proposed as a mechanistic link between sleep disruption and AD, and in animal models glymphatic impairment is sufficient to drive the development of AD pathology. It remains unknown whether the glymphatic system clears amyloid beta (Aβ) and tau from the brain in humans. This study directly tested the hypothesis that sleep-active glymphatic clearance increases morning plasma AD biomarker levels. In a multi-site randomized crossover clinical trial, participants (N=39) underwent overnight in-laboratory conditions of normal sleep and sleep deprivation following instrumentation that included a novel device to measure sleep features by electroencephalography (EEG), cerebrovascular compliance by measurement of pulse transit time (PTT), and brain parenchymal resistance to glymphatic flow (R P ) by transcranial multifrequency impedance spectroscopy. We evaluated whether R P , sleep EEG features, PTT, and heart rate variability (HRV) predicted overnight changes in plasma AD biomarker (Aβ40, Aβ42, np-tau181, np-tau217 and p-tau181) levels. We found that changes in R P , PTT, HRV and EEG delta power in a multivariate linear mixed model predicted sleep-associated overnight changes in Aβ40 (p=0.013), Aβ42 (p<0.001), np-tau181 (p<0.001), np-tau217 (p<0.001) and p-tau181 (p<0.001). The predicted changes replicated those from a multicompartment model based on published data on synaptic-metabolic release and clearance of Aβ and tau to the plasma. Sensitivity analysis demonstrated that while morning biomarker levels were altered by both the synaptic-metabolic release and clearance of Aβ and tau, during sleep glymphatic clearance was the dominant influence. In contrast, during sleep deprivation (waking) while glymphatic clearance was a contributor, Aβ and tau release was the dominant factor explaining variance in morning plasma Aβ and tau levels. Our findings show that elements of sleep-active physiology, in particular decreased brain parenchymal resistance, facilitates the overnight clearance of AD biomarkers to plasma, supporting a role for glymphatic clearance in these processes, and suggesting the enhancement of glymphatic function as a therapeutic target to reduce the development and progression of AD pathology in at-risk populations.