Disrupted or insufficient sleep is a well-documented risk factor for Alzheimer's disease (AD) and related dementias. Previous studies in our lab and others have shown that chronic fragmentation of the daily sleep-wake rhythm in mice can accelerate the development of AD-related neuropathology in the brain, including increases in the levels of amyloid-β (Aβ). Although sleep is known to increase clearance of Aβ via the glymphatic system, little is known about the effect of sleep on Aβ production and the role this might play in amyloid deposition. To examine the relationship of Aβ production and its interaction with sleep and sleep dysfunction, we treated mice from an APP × PS1 mutant knock-in line (APP × PS1) with an inhibitor of γ-secretase (LY-450,139; Semagacestat®) during a protocol of mild sleep fragmentation (SF). Compared to the male mice, the female mice slept less, and had more Aβ pathology. Semagacestat treatment reduced Aβ, but only in the most soluble extractable fraction. Although the female mice showed an increase in the amount of Aβ following SF, this effect was blocked by Semagacestat, an effect that was not seen in the male mice. SF also led to a significant, sex-dependent changes in the relative amounts of C-terminal fragments of the amyloid precursor protein, the immediate substrate of the γ-secretase enzyme. These findings indicate that the relationship between disruption of the daily sleep-wake rhythm and the development of AD-related pathology is complex, and may involve unappreciated interactions with biological sex. Consideration of these factors is necessary for a better understanding of AD risk, especially the elevated risk in women. ΔNLh/ΔNLh P264L/P264L
