Archived
This content is available here for research, reference, and/or recordkeeping.
Abstract
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.
Document Type
Article
Publication Date
2026
Digital Object Identifier (DOI)
https://doi.org/10.1002/alz.71579
Funding Information
BrightFocus Foundation, Grant/Award Numbers: R01AG068330, R01AG093847, A20201775S; Coins for Alzheimer’s Research Trust, Grant/Award Number: P30AG072946; Cure Alzheimer’s Fund, Grant/Award Number: T32NS115704; Institutional Development Award; NIGMS; NIH, Grant/Award Number: P30GM127211; NIH Center of Biomedical Research Excellence (COBRE) in CNS Metabolism, Grant/Award Number: P20GM148326
Repository Citation
Constantino, Nicholas J.; Irmen, Riley E.; Lanning, Matthew J.; Turner, Sierra M.; Ashley, Clair C.; Carroll, Caitlin M.; Neary, Evan M.; Rubinow, Dave; Snipes, J. Andy; and Macauley, Shannon L., "Early microglial response to amyloid plaques drives sleep loss in Alzheimer’s disease" (2026). Physiology Faculty Publications. 199.
https://uknowledge.uky.edu/physiology_facpub/199
Notes/Citation Information
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2026 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.