Sleep and Brain Health: Insights from Biomarker Research - Tim Lyckenvik

Background
The glymphatic hypothesis has built a convincing case that sleep promotes clearance of Alzheimer’s disease (AD)-related proteins, supported by elegant mechanistic rodent studies. However, direct human evidence remains limited.

Objective
To determine how sleep versus total sleep deprivation affects CSF concentrations of proteins linked to AD pathology, neuronal integrity, and glial activation in humans.

Methods
Twelve healthy adults (20–40 years) completed three experimentally controlled sleep conditions in a randomized crossover design: (a) normal sleep with morning CSF sampling, (b) normal sleep with afternoon CSF sampling, and (c) total sleep deprivation with morning CSF sampling. Sleep and wakefulness were verified using polysomnography and actigraphy. Amyloid-β (Aβ38/40/42) and tau (t-tau, p-tau181) were measured as AD-related proteostatic markers. Neurofilament light chain (NfL) and GFAP were included as markers of neuronal injury and astrocytic activation. Orexin-A was measured as a wake-promoting neuropeptide proposed to influence AD-related protein dynamics. Albumin and osmolality were assessed as indicators of CSF dynamics.

Results
CSF concentrations of Aβ40, Aβ42, and p-tau were significantly lower after sleep compared with sleep deprivation, with similar trends for Aβ38 and t-tau. In contrast, NfL and GFAP remained stable. CSF albumin increased after sleep. Orexin-A increased markedly during sleep deprivation but did not consistently correlate with Aβ or tau.

Conclusion
Sleep reduced CSF concentrations of Aβ and tau without parallel changes in NfL or GFAP, suggesting that sleep-related CSF protein regulation is not uniform across protein classes. Increased CSF albumin supports elevated CSF turnover during sleep. These findings are consistent with a model in which slow-wave sleep promotes selective proteostatic regulation, potentially facilitated by enhanced solute mobility. Orexin appears to primarily oppose sleep pressure rather than directly mediating AD-related biomarker dynamics.