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Peer-reviewedCC BY-NC-NDAlzheimer s & Dementia

Early microglial response to amyloid plaques drives sleep loss in Alzheimer's disease

  • Nicholas J. Constantino1,2
  • Riley E. Irmen2
  • Matthew J. Lanning2
  • Sierra M. Turner2
  • Clair C. Ashley2
  • Caitlin M. Carroll3
  • Evan M. Neary2
  • Dave Rubinow4
  • James Andy Snipes2
  • Shannon L. Macauley1,2,5
5 affiliations
  1. 1Department of Neuroscience University of Kentucky Lexington Kentucky USA
  2. 2Department of Physiology University of Kentucky Lexington Kentucky USA
  3. 3Department of Psychiatry Alzheimer's Disease Research Center Wake Forest University School of Medicine Winston Salem North Carolina USA
  4. 4LifeCanvas Technologies Cambridge Massachusetts USA
  5. 5Sanders Brown Center of Aging University of Kentucky Lexington Kentucky USA
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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.

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Cite

BibTeXRIS
BibTeX
@article{constantino2026early,
  title = {{Early microglial response to amyloid plaques drives sleep loss in Alzheimer's disease}},
  author = {Nicholas J. Constantino and Riley E. Irmen and Matthew J. Lanning and Sierra M. Turner and Clair C. Ashley and Caitlin M. Carroll and Evan M. Neary and Dave Rubinow and James Andy Snipes and Shannon L. Macauley},
  journal = {Alzheimer s \& Dementia},
  year = {2026},
  month = jun,
  doi = {10.1002/alz.71579},
  url = {https://doi.org/10.1002/alz.71579},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Early microglial response to amyloid plaques drives sleep loss in Alzheimer's disease
AU  - Nicholas J. Constantino
AU  - Riley E. Irmen
AU  - Matthew J. Lanning
AU  - Sierra M. Turner
AU  - Clair C. Ashley
AU  - Caitlin M. Carroll
AU  - Evan M. Neary
AU  - Dave Rubinow
AU  - James Andy Snipes
AU  - Shannon L. Macauley
PY  - 2026
DA  - 2026/06/01
JO  - Alzheimer s & Dementia
DO  - 10.1002/alz.71579
UR  - https://doi.org/10.1002/alz.71579
AB  - 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.
SN  - 1552-5260
SN  - 1552-5279
ER  -