Glial cytokine modulation improves sleep and circadian disruption in female SAA knock-in mice of Alzheimer's-related pathology.

INTRODUCTION: Sleep and circadian disturbances are early Alzheimer's disease (AD) features, yet mechanisms linking amyloid pathology, neuroinflammation, and sex differences remain unclear. METHODS: We longitudinally assessed sleep, circadian rhythms, and cognition in female and male hAPPSAA knock-in and control mice from 2 to 19 months using piezoelectric monitoring. Aged mice (15 months) received MW151, a glial cytokine inhibitor (2.5 mg/kg, every other day, 6 weeks). RESULTS: Only females exhibited midlife reductions in light-phase sleep, increased rhythm fragmentation, and reduced rhythm stability, coinciding with selective reversal learning deficits, effects independent of amyloid or cytokine burden. MW151 increased light-phase sleep and reduced cortical TNF-α without altering amyloid beta (Aβ) accumulation. DISCUSSION: HAPPSAA mice recapitulate female-predominant non-cognitive AD features, including sleep fragmentation and circadian instability preceding memory deficits. Sleep improved within weeks of MW151 treatment without Aβ reductions, implicating neuroinflammatory signaling as a rapid, modifiable driver of AD-related sleep disruption.