Slow Wave Sleep Reduces CSF Concentrations of Beta-amyloid and Tau: A Randomized Crossover Study in Healthy Adults

Background Slow-wave sleep has been proposed to facilitate the removal of proteins, implicated in neurodegeneration, from the brain. While mechanistic evidence from animal models is accumulating, direct human data on how slow-wave sleep shapes cerebrospinal fluid (CSF) proteostasis remain limited, constraining our understanding of physiological resilience to neurodegenerative disease.

Twelve healthy adults (aged 20–40 years) underwent CSF sampling following three controlled sleep conditions in a randomized crossover design; (1) one night of sleep followed by afternoon CSF sampling, (2) one night of sleep followed by morning CSF sampling, and (3) one night of total sleep deprivation followed by morning CSF sampling. Sleep and wakefulness were verified using polysomnography and actigraphy, with >4-week washout periods between conditions. Measured CSF biomarkers included Alzheimer’s disease-related proteins: beta-amyloid isoforms (Aβ38, Aβ40, and Aβ42), total and phosphorylated tau, glial fibrillary acidic protein (GFAP), and neurofilament light, as well as orexin, albumin (also measured in serum), and osmolality. Differences between conditions were assessed using Friedman tests with Dunn’s post hoc correction.

CSF levels of Aβ and tau tended to be consistently lower after sleep compared with both afternoon sampling and post-sleep deprivation. Concurrently, CSF albumin levels increased after sleep, while neurofilament light and GFAP remained unchanged. Orexin levels rose markedly during sleep deprivation but showed no circadian variation.

These findings support a model in which slow wave sleep enhances CSF turnover, reducing concentrations of specific proteins, including Aβ and tau. Understanding how sleep regulates the homeostasis of neurodegeneration-related proteins may inform strategies to mitigate disease progression. Competing Interest Statement HZ has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). List of abbreviations - CSF - cerebrospinal fluid - GFAP - glial fibrillary acidic protein - AD - Alzheimer’s disease - PD - Parkinson’s disease - Aβ - beta-amyloid - TSD - total sleep deprivation - SWS - slow-wave sleep - p-tau - phosphorylated tau - t-tau - total-tau - NfL - neurofilament light chain - PSG - polysomnography - RIA - radioimmunoassay - ISEs - ion-selective electrodes - IQR - interquartile range - Aβ38 - amyloid β (1-38) - Aβ40 - amyloid β (1-40) - Aβ42 - amyloid β (1-42) - Aβ42:40 - ratio of beta amyloid 42/40