Prevention of cognitive decline is a public health priority and there is a call to initiate effective preventative interventions in the middle decades. For midlife women, the menopausal transition (MT) combines endocrine and chronological aging with unique mechanistic impacts on memory function that could make the female brain vulnerable to development of dementia. Thus, the MT represents a critical window for the early detection of cognitive vulnerability, and for implementation of preventive interventions. Sleep is critical for memory formation, with specific electrophysiological features of sleep, including sleep spindles (12-15Hz) and slow oscillations (SOs, 0.5-1Hz), causally implicated in this process. Research into lifespan development interactions between sex hormones, sleep and memory is lacking, particular in the midlife period when decreases in sleep and memory are noted, but the biological systems are still intact. Here, we propose to investigate mechanisms of sex hormone impact on, and also consider potential sex differences in, sleep-related memory consolidation in young and midlife MT women. We also propose a translational approach to investigate the potential efficacy of a sleep-related intervention to improve declarative memory in midlife MT women. An under-appreciated possibility supported by our pilot data is that the withdrawal of sex hormones during menopause may contribute to cognitive decline in women through diminution of memory-related sleep waveforms. Thus, degraded sleep-dependent learning could represent an important feature of cognitive aging that is modifiable through non-invasive, non-pharmacological routes by enhancing sleep via targeted interventions. We hypothesize that enhancement of these sleep waveforms in midlife could stave off cognitive decline in women. Here, we propose a novel experimental approach to investigate 1) lifespan developmental mechanisms of sex hormone influence on sleep-dependent memory consolidation through specific sleep waveforms; 2) sex differences in sleep-dependent memory consolidation; 3) effectiveness of a unique intervention (auditory-based closed-loop memory reactivation) in boosting sleep waveforms and memory consolidation in women in the MT. This proposal has the potential to open new avenues into a mechanistic understanding of the interaction between sex hormones, sleep, and cognition, which could lead to the development of unique non-invasive, sleep-focused interventions to counteract cognitive decline. Outcomes of these studies will have broad impact given that 1) there are >850M women aged 40-50 years worldwide, the majority of whom will enter the MT by age 55; 2) 70M Americans suffer from disordered sleep at an estimated annual cost of $150B2; 3) The US population is aging and it is projected that by the year 2050 more than 13.5M individuals in the US alone will manifest Alzheimer Disease, necessitating an urgent need for preventative therapy that can be applied during midlife to counteract progression to memory-related disorders of aging and reduce future disease burden.
The proposed research will serve the mission of the National Institutes of Health by expanding the basic science knowledge of pathological memory and in investigating translational approaches to prevention and treatment of conditions that impact memory in clinical and at risk populations (e.g., older adults, dementia and Alzheimer's disease). We will determine lifespan developmental mechanisms of sex and sex hormone impact on memory in young and midlife women and men, and use a novel sleep-boosting intervention to further understand the potential protective role of sleep against cognitive decline. Knowledge gained from this proposal could lead to the development of unique non-invasive, sleep-focused interventions to slow cognitive decline and ultimately progression to Alzheimer's disease in aging women.