Administrative Supplement to Sleep Fragmentation and Alzheimer's Disease

This is an Administrative Supplement request in response to NOT-OD-22-030 “Research on Sex and / or Gender Influences” for R01 AG068215-02 “Sleep Fragmentation and Alzheimer’s Disease”. Funds are requested to perform RNA-sequencing studies and biochemical analyses on additional comparison groups of male and female mice undergoing the sleep evaluation and fragmentation procedures proposed within the scope of R01 AG068215, with the addition of a gonadectomy procedure to delineate the sex-based factors (NOT-OD-15-102) that underlie our novel observations of surprising sex differences. Chronic sleep disruption, resulting from work schedules, noise exposure, family obligations, sleep disorders, or lifestyle choices, is a pervasive feature of contemporary life. Sleep problems affect up to 40% of Alzheimer’s disease (AD) patients, may precede cognitive impairments by more than a decade, and worsen as the disease progresses. As well as affecting mood and well-being, sleep disruption may drive the development of AD-related neuropathology. Numerous studies have indicated that women are both at greater risk of developing Alzheimer’s disease and related dementias, and also show increased propensity to develop a range of sleep disorders post- menopause. Our studies of AD mouse models show that induced and spontaneously occurring sleep fragmentation (SF) is associated with more severe AD-related neuropathology. Our recent experiments discovered a surprising sex difference, in that the female mice harboring dominant AD mutations were significantly more susceptible to sleep disruption in comparison to male mice. The mutant female mice also showed differences in their undisturbed sleep. A re-analysis of our earlier published data indicated that a similar sleep disturbance was also present in female mice of a different strain, carrying different AD mutations, strongly suggesting that this might be a general phenomenon that could shed light on sex specific risk factors connecting AD and sleep dysfunction. As the parent R01 considered sex as a variable, but was not designed to explore sex differences, we hypothesize that an increased sample size (sex-based research approach 2) will provide sufficient power to discover possible contributing mechanism(s), and guide future studies. This supplemental project has two specific aims: (1) to explore the mechanism of female susceptibility to SF in an AD mouse model, and (2) to explore the shared mechanism of female specific sleep dysfunction in two different AD-related mouse lines. This supplemental funding request for Pre-Clinical Research is aligned with Strategic Objectives 1.1, 1.2, and 1.4 of the Trans-NIH Strategic Plan for Women’s Health Research.