Association of Rest-Activity Rhythm and Risk of DevelopingDementia or Mild Cognitive Impairment in the Middle-Aged andOlder Population:Prospective Cohort Study

Background: The relationship between 24-hour rest-activity rhythms (RARs) and risk for dementia or mild cognitive impairment(MCI) remains an area of growing interest. Previous studies were often limited by small sample sizes, short follow-ups, and olderparticipants. More studies are required to fully explore the link between disrupted RARs and dementia or MCI in middle-agedand older adults. Objective: We leveraged the UK Biobank data to examine how RAR disturbances correlate with the risk of developing dementiaand MCI in middle-aged and older adults. Methods: We analyzed the data of 91,517 UK Biobank participants aged between 43 and 79 years. Wrist actigraphy recordingswere used to derive nonparametric RAR metrics, including the activity level of the most active 10-hour period (M10) and itsmidpoint, the activity level of the least active 5-hour period (L5) and its midpoint, relative amplitude (RA) of the 24-hour cycle[RA=(M10-L5)/(M10+L5)], interdaily stability, and intradaily variability, as well as the amplitude and acrophase of 24-hourrhythms (cosinor analysis). We used Cox proportional hazards models to examine the associations between baseline RAR andsubsequent incidence of dementia or MCI, adjusting for demographic characteristics, comorbidities, lifestyle factors, shiftworkstatus, and genetic risk for Alzheimer's disease. Results: During the follow-up of up to 7.5 years, 555 participants developed MCI or dementia. The dementia or MCI riskincreased for those with lower M10 activity (hazard ratio [HR] 1.28, 95% CI 1.14-1.44, per 1-SD decrease), higher L5 activity(HR 1.15, 95% CI 1.10-1.21, per 1-SD increase), lower RA (HR 1.23, 95% CI 1.16-1.29, per 1-SD decrease), lower amplitude(HR 1.32, 95% CI 1.17-1.49, per 1-SD decrease), and higher intradaily variability (HR 1.14, 95% CI 1.05-1.24, per 1-SD increase)as well as advanced L5 midpoint (HR 0.92, 95% CI 0.85-0.99, per 1-SD advance). These associations were similar in people aged <70 and >70 years, and in non-shift workers, and they were independent of genetic and cardiovascular risk factors. Nosignificant associations were observed for M10 midpoint, interdaily stability, or acrophase. Conclusions: Based on findings from a large sample of middle-to-older adults with objective RAR assessment and almost8-years of follow-up, we suggest that suppressed and fragmented daily activity rhythms precede the onset of dementia or MCIand may serve as risk biomarkers for preclinical dementia in middle-aged and older adults