Sleep reduces CSF concentrations of beta-amyloid and tau: a randomized crossover study in healthy adults

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 tau, tau phosphorylated at amino acid 181 (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain, 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 and did not track with biomarker levels. These findings support a model in which slow-wave sleep selectively reduces CSF concentrations of Aβ and tau, potentially through enhanced solute mobility and receptor-mediated clearance. Unchanged levels of NfL and GFAP argue against bulk clearance. Orexin may primarily function to oppose sleep pressure rather than directly regulate proteostasis. These hypotheses merit direct testing to inform strategies for delaying pathological protein accumulation in neurodegenerative disease.