Chronic Sleep Fragmentation Differentially Affects Alzheimer’s Disease Pathology in Male and Female APP^SAA Knock-in Mice

Introduction: Sleep fragmentation often precedes Alzheimer’s disease (AD) diagnosis and represents a potential modifiable risk factor, especially among women who have higher prevalence of both sleep disorders and AD. Methods: This study investigated how chronic sleep fragmentation affects neuroinflammation and amyloid-beta (Aβ) accumulation in male and female APP^SAA knock-in mice, a physiologically relevant AD model expressing APP at normal levels. APP^SAA mice of both sexes (N=8/sex/strain, 8 months old) underwent either 5 weeks of chronic sleep fragmentation administered during the light phase using an automated sweeper system or undisturbed sleep. Sleep-wake patterns and circadian rhythms were monitored using piezoelectric sensors. Following intervention, we assessed neuroinflammatory markers via immunohistochemistry and multiplex cytokine analysis, Aβ levels in different solubility fractions, and Aβ plaque characteristics through digital pathology. Results: Sleep fragmentation effectively disrupted sleep patterns in both sexes, reducing light-phase sleep and increasing intradaily variability. Sleep fragmentation increased GFAP immunoreactivity in both sexes, with larger effects in females than males. Surprisingly, sleep fragmentation decreased expression of the microglial activation markers MHCII and Dectin-1 in males. Pro-inflammatory cytokines (IL-1β, CCL2, CXCL2) were significantly elevated following sleep fragmentation, with distinct regional and sex-specific patterns. In females, sleep fragmentation increased PBS-soluble and formic acid-soluble Aβ in the neocortex and medium-sized plaque density in the hippocampus, while males showed decreased detergent-soluble Aβ in the neocortex following sleep fragmentation. Discussion: Chronic sleep fragmentation exacerbates AD-related pathology in APP^SAA mice in a sex-dependent manner, with females showing greater vulnerability to Aβ accumulation and astrocyte reactivity following sleep disruption. These findings suggest that environmental sleep disruptions may contribute to the higher prevalence of AD in women and highlight the importance of addressing sleep fragmentation as a modifiable risk factor for AD.