Sex differences in sleep fragmentation in 5xFAD mice

Sleep alterations have long been associated with Alzheimer's disease (AD), but whether it is an early symptom or only develops later in the pathological progression remains unknown. To study this, 5xFAD heterozygous (Het) mice, a transgenic model of amyloid overexpression, and wild-type (WT) littermates at 1, 2, 3, 4 and 6 months of age were assessed within instrumented home cages to noninvasively score 3-state sleep using respirations and gross body movements during the dark cycle. Progressive alterations in dark cycle sleep architecture were identified in Het animals as early as 1 month of age. Compared to WT littermates, Het mice exhibited increased sleep fragmentation and more microarousals. These effects were more pronounced in females than in males. Across ages, Het mice showed increased time awake and decreased sleep time, latency to rapid eye movement (REM) and total time in REM, although percent sleep time spent in REM did not differ significantly from WT controls. Most genotype differences widened by 6 months of age. Female mice exhibited shorter total time in non-REM relative to males. Additionally, females spent a greater proportion of time in wake, findings consistent with prior literature on WT sex differences in sleep vulnerability. Given that transgene expression was evidenced by day 15 of the 5xFAD Het and escalated with age, the observed early sleep dysregulation was likely reflective of the accumulation of soluble amyloid-beta oligomers. These results highlight early, sex-specific disruptions in dark cycle sleep that may serve as preclinical markers of AD-related pathology.