Early microglial response to amyloid plaques drives sleep loss in Alzheimer's disease
- Alzheimers Dement. 2026 Jun;22(6):e71579. doi: 10.1002/alz.71579.
- 1. Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
- 2. Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA.
- 3. Department of Psychiatry, Alzheimer's Disease Research Center, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA.
- 4. LifeCanvas Technologies, Cambridge, Massachusetts, USA.
- 5. Sanders Brown Center of Aging, University of Kentucky, Lexington, Kentucky, USA.
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.