Science

Nicholas J. Constantino, Riley E. Irmen, Matthew J. Lanning, Sierra M. Turner, Clair C. Ashley, Caitlin M. Carroll, Evan M. Neary, Dave Rubinow, J. Andy Snipes, Shannon L. Macauley

INTRODUCTION
Sleep disruption is an early feature of Alzheimer’s disease (AD), but the cellular mechanisms linking amyloid pathology to sleep loss remain unclear.

METHODS
Electroencephalography/electromyography (EEG/EMG) recordings, quantitative EEG analysis, and sleep deprivation were performed in APPswe/PSEN1dE9 (APP/PS1) mice at different stages of pathology relative to normal aging. Amyloid burden and microglial density were quantified with whole-brain light-sheet microscopy. CSF1R-mediated microglial depletion explored effects of microglia on sleep loss.

RESULTS
Amyloid plaques caused non–rapid eye movement (NREM) sleep loss that did not worsen with increased plaque burden. Aging reduced REM sleep and eliminated sleep rebound. Amyloid pathology was associated with cortical hyperexcitability, network desynchrony, and microglial expansion extending beyond plaque-bearing regions into thalamocortical and white matter networks governing sleep–wake dynamics. Microglial depletion restored > 2 hours of sleep per day without altering amyloid burden.

DISCUSSION
Microglia are a causal, reversible driver of amyloid-associated sleep loss, positioning sleep and EEG-based metrics as sensitive biomarkers of presymptomatic AD.

Highlights

– Non–rapid eye movement (NREM) sleep loss emerges with amyloid plaques and does not scale with plaque burden.
– Amyloid plaques disrupt NREM, but not REM sleep.
– Aging reduces REM sleep and homeostatic sleep rebound.
– Microglia drive amyloid-related NREM loss; depletion increases sleep by ∼2 hrs/day.
– Electroencephalography (EEG) signatures distinguish amyloid pathology from aging as early biomarkers of disease.