Circadian rest-activity rhythm and longitudinal brain changes underlying late-life cognitive decline

Aim: The neurobiological substrates underlying the relationship of circadian rest-activity rhythm (RAR) alteration with accelerated late-life cognitive decline are not clearly understood. In the present study, the longitudinal relationship of objectively measured circadian RAR with in vivo Alzheimer disease (AD) pathologies and cerebrovascular injury was investigated in older adults without dementia. Methods: The present study included 129 participants without dementia who participated in the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease) cohort. All participants underwent actigraphy at baseline and two consecutive [C-11] Pittsburgh compound-B positron emission tomography (PET), [F-18] fluorodeoxyglucose-PET, magnetic resonance imaging, and Mini-Mental State Examination (MMSE) at baseline and at a 2-year follow-up assessment. The associations of circadian RAR with annualized change in neuroimaging measures including global amyloid-beta retention, AD-signature region cerebral glucose metabolism (AD-CM), and white matter hyperintensity volume were examined. Results: Delayed acrophase at baseline was significantly associated with greater annualized decline of AD-CM over a 2-year period, but not with that of other neuroimaging measures. In contrast, other circadian RAR parameters at baseline had no association with annualized change of any neuroimaging measures. Annualized decline of AD-CM was also significantly positively associated with the annual change in MMSE scores. Furthermore, a mediation analysis showed that greater reduction in AD-CM mediated the effect of delayed acrophase at baseline on faster decline of MMSE score. Conclusion: The findings indicate that delayed acrophase in late life may cause or predict hypometabolism at AD-signature brain regions, which underlies cognitive decline in the near future.