Microglia Depletion Restores >2 Hours Daily Sleep in 6- and 18-Month Alzheimer's Model Mice

University of Kentucky researchers compared APP/PS1 mice to wild-type controls at 6 and 18 months. They administered a CSF1R inhibitor to ablate most microglia, then recorded sleep architecture with EEG/EMG and quantified inflammatory cytokines plus plaque burden via immunohistochemistry. Amyloid load remained unchanged while sleep duration and quality metrics normalized toward wild-type levels.

Data show that plaque-associated microglial activation drives IL-1β and TNF-α surges that fragment sleep; elimination of these cells cut cytokine levels 60-70% and added 127 minutes of total sleep time at 6 months and 138 minutes at 18 months. Prior anti-amyloid antibody trials that cleared plaques but left microglia intact produced smaller sleep gains, indicating the immune response—not plaque mass—dominates the phenotype.

The finding reframes sleep disruption as a reversible secondary inflammatory process rather than irreversible neuronal loss. It aligns with CSF1R-inhibitor data in other neurodegeneration models where microglial removal improved circuit function without addressing primary aggregates. Operational implication: short-term microglial modulation could be paired with existing symptomatic therapies while longer-term safety of sustained depletion is tested.

Next steps require dose-response curves in non-human primates and CSF biomarker panels from ongoing human CSF1R trials to confirm translation before any mild-AD pilot.