AS629 - Rest-activity rhythms, dementia and Alzheimer's disease in older men and women: the role of metabolism and inflammation

Investigator Names and Contact Information

Qian Xiao (qian-xiao@uiowa.edu)

Andrea LaCroix (alacroix@health.ucsd.edu)

Introduction/Intent

Sleep and circadian rhythms play crucial role in regulating metabolism and immune function, both of which are critical for cardiovascular and cognitive health. Earlier studies have suggested that sleep deficiencies and circadian impairment may be important risk factors for cardiovascular disease and cognitive decline in the older population. Although previous studies have provided important insights into the important role of sleep in cardiometabolic and cognitive health, most relied on self-reported sleep duration and quality, which are not only prone to recall bias, but fail to capture the overall structure of diurnal rhythms. Moreover, there has been limited investigations to examine underlying mechanisms driving health effects of poor sleep and circadian dysfunction in the elderly, although our pilot study using metabolomics identified multiple metabolite markers that were associated with circadian phase. Some of the markers have been previously linked with chronic conditions, supporting a role of metabolic pathways in the relationship between sleep and health. In two unique and complimentary cohorts of older adults, the Osteoporotic Fractures in Men Study and the Women’s Health Initiative, we propose to examine self-report and actigraphy sleep and circadian measurements in relation to CVD and cognitive decline, with special emphasis on identifying metabolomic and inflammatory profiles to elucidate underlying mechanisms for aging men and women.

Specific Aims:

1. Describe sex-specific relationships between sleep, rest-activity rhythms, and health outcomes of cognitive decline.
2. Examine metabolic and inflammatory markers in relation to sleep and rest-activity rhythms.
3. Examine metabolic and inflammatory markers in relation to cognitive decline.
4. Build predictive models of risk for cognitive decline in aging men and women.

Pilot Aims:

Aim 1 Determine gender-specific relationships between rest-activity rhythms and long-term cognitive outcomes in women. Hypothesis 1: Weakened rest-activity rhythms (including altered timing and lower amplitude and rhythmicity) will be associated with increased incidence of ADRD, and more rapid cognitive decline over 5-12 years.

Previously published studies in MrOS have identified multiple rest-activity rhythm characteristics that were associated with cognitive outcomes in men. We will apply the same algorithms to characterize rest-activity rhythms to examine whether and how they predict cognitive outcomes in older women in WHI.

Aim 2 Identify metabolomics signatures that are commonly associated with both rest-activity rhythms and incident ADRD in both men and women. Hypothesis 2: Weakened rest-activity rhythms and incident ADRD will be associated with alterations in common metabolomic profiles, such as increases in γ-glutamyl dipeptides, bile acids, fatty acids and acylcarnitines, and decreases in PUFA.