Circadian Rest-Activity Rhythms, Cognition, and Alzheimer Disease Dementia in Adults With Down Syndrome

There is a paucity of research on the role of circadian rhythm disruption in Alzheimer disease (AD)-related cognitive impairments in adults with Down syndrome (DS). The aim of this study was to examine the association of the 24-hour rest-activity rhythm with cognition, dementia symptoms, and clinical AD status in adults with DS.

In this cross-sectional study, adults with DS aged 25-61 years in the Alzheimer's Biomarkers Consortium-Down Syndrome underwent wrist-worn actigraphy (≥4 days) and cognitive assessment. Primary variables included interdaily stability, intradaily variability, relative amplitude, most active 10-hour period (M10), and least active 5-hour period (L5). Secondary measures included coefficient of variation of total sleep time, sleep midpoint, sleep efficiency, and the sleep regularity index. Cognitive outcomes included modified Cued Recall Test (mCRT), Wechsler Block Design with Haxby Extension (Block Design), Purdue Pegboard, Cat and Dog Modified Stroop Task, DS Mental Status Examination (DSMSE), National Task Group-Early Detection Screen for Dementia (NTG-EDSD), Dementia Questionnaire for People with Learning Disabilities (DLD), and clinical AD status based on a case consensus process (stable vs mild cognitive impairment [MCI]/dementia). Linear and logistic regression models were adjusted for age, sex, intellectual disability level, site, and obstructive sleep apnea severity, with false discovery rate (FDR) correction.

Of 115 participants (mean age 40.0 ± 9.2 years; 43.5% female), higher interdaily stability was associated with higher DSMSE scores B = 20.6 (95% CI 5.0-36.2). Higher intradaily variability was associated with worse cognitive performance and increased dementia symptoms: mCRT B = -9.2 (95% CI -15.2 to -3.1), Block Design B = -11.0 (95% CI -19.0 to -3.0), DSMSE B = -12.0 (95% CI -20.1 to -3.9), and DLD-cognitive B = 6.3 (95% CI 3.0-10.5). Lower M10 was associated with increased dementia symptoms: NTG-EDSD B = -0.004 (95% CI -0.008 to -0.001); DLD-cognitive B = -0.004 (95% CI -0.006 to -0.001), and DLD-social B = -0.003 (95% CI -0.005 to -0.0008). All associations remained significant after FDR correction (p < 0.05). Fifteen participants had MCI/dementia. Higher intradaily variability was associated with increased odds of MCI/dementia (OR: 1.45; 95% CI 1.04-2.29) although this was not significant after FDR correction.

Fragmentation and low amplitude of the 24-hour rest-activity rhythm are associated with AD-related cognitive impairment, dementia symptoms, and increased odds of MCI/dementia in adults with DS. Circadian rhythm disruption may contribute to AD-related outcomes in adults with DS and potentially serve as a modifiable risk factor.