White matter microstructure statistically mediates associations between circadian rest/activity rhythms and cognition...

Aging is associated with disruptions in circadian rhythms, lower brain white matter integrity, and cognitive changes. However, whether white matter integrity serves as a potential mechanism linking circadian dysfunction to age-related cognitive abilities in older adults is unclear. We investigated cross-sectional associations of actigraphic circadian rest/activity rhythms (RARs) with whole-brain white matter tract fractional anisotropy (FA) and executive function performance in 156 older adults without dementia from the BIOCARD study (mean age = 71.3 years, including 19 with mild cognitive impairment and 137 cognitively unimpaired). We studied non-parametric metrics of RAR strength (relative amplitude [RA]), day-to-day stability (interdaily stability [IS]), and fragmentation (intradaily variability [IV]). After adjusting for age, sex, education, APOE-e4 genotype, vascular risk, and diagnostic group, we found that greater rhythm strength (higher RA) was associated with better executive function. Additionally, higher rhythm strength (RA) and stability (IS) were associated with greater whole-brain FA, reflecting better white matter integrity, whereas greater fragmentation (IV) was associated with lower FA. Greater white matter integrity was also associated with better executive function and statistically mediated the association of higher RA with better executive function performance. Findings underscore the relationships between RAR strength and cognitive health in older adults and suggest that white matter integrity may be a key mechanism underlying these associations.