Independent Associations Of Sleep And Physical Activity With Cognition Are Mediated By Hippocampal Microstructure In Middle-aged And Older Adults

PURPOSE: Better sleep and higher physical activity levels are both associated with improved cognitive performance in older adults at heightened risk of cognitive impairment; however, the neural mechanisms that support these relationships remain poorly understood. Medial temporal lobe (MTL) microstructural integrity, measurable through diffusion imaging, may serve as an earlier and more sensitive indicator of neurodegenerative processes than MTL volume or visible atrophy. METHODS: This study investigated cross-sectional associations of actigraphic estimates of physical activity and sleep with cognition and diffusion imaging-based measures of MTL microstructural integrity in dementia free adults. Participants were 132 older adults from the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) cohort study (119 cognitively unimpaired and 13 with mild cognitive impairment; mean age = 70.8 years). Multiple linear regression analyses assessed the relationships between total volume of physical activity (TVPA), total sleep time (TST), and sleep efficiency (SE) with cognitive performance and MTL microstructural integrity, adjusting for age, sex, education, diagnostic status, vascular risk, APOE-e4 status, MTL volume, and Alzheimer’s pathology. RESULTS: Results showed that greater TVPA and SE were both independently associated with higher hippocampal microstructural integrity (indicated by lower mean diffusivity; β = -.256, p = .002 and β = -.247, p = .002, respectively) and enhanced visuospatial processing (β = .212, p = .015 and β = .233, p = .007, respectively), independent of hippocampal volume and amyloid-beta (Aβ) burden measured by Positron Emission Tomography. Moreover, hippocampal microstructure mediated the relationships between physical activity and sleep with visuospatial abilities (indirect effect 95% CI [.007, .131] for physical activity and [.006, .121] for sleep), independent of MTL volume and Aβ burden. CONCLUSIONS: These findings suggest that physical activity and sleep are independently associated with cognitive performance, and that hippocampal microstructural integrity may be an underlying mechanism supporting these associations independent of structural atrophy and Alzheimer's pathology burden. Supported by: This work was supported by the National Institutes of Health [grant numbers U19-AG033655, P30-AG005146].