Poor sleep is implicated in the development of Alzheimers disease (AD) pathology and cognitive impairment. The glymphatic system has been proposed as a 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 (Ab) and tau from the brain in humans. In a multi-site randomized crossover clinical trial (N=39), participants underwent overnight in-laboratory conditions of normal sleep and sleep deprivation following instrumentation that included a novel device to measure brain parenchymal resistance to glymphatic flow (RP) by transcranial multifrequency impedance spectroscopy and sleep electroencephalography (EEG). This study directly tested the hypothesis that sleep-active glymphatic clearance increases morning plasma AD biomarker levels. The primary outcomes were the change in plasma levels of AD biomarkers (Ab40, Ab42, np-tau181, np-tau217 and p-tau181) from evening to morning predicted by RP, sleep EEG features, and heart rate. We found that changes in RP, heart rate and EEG delta power predicted changes in Ab42 (p<0.001), np-tau181 (p=0.002), 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 Ab; and tau efflux from brain to plasma. Our findings show that elements of sleep-active physiology, in particular decreased brain parenchymal resistance, facilitates the 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.

The authors JJI, LG, TS, AC, MML declare the existence of financial and incentive stock options competing interests. The author EL declare the existence of financial competing interests.

NCT06060054 and NCT06222385

This study was funded by Applied Cognition.

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IRB of University of Florida gave ethical approval for this work (IRB No. 202201364) IRB of Western Institutional Review Board gave ethical approval for this work (IRB No. 20225818).

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