Association of the Sleep Regularity Index With Incident Dementia and Brain Volume
Abstract
Background and Objectives
Irregular sleep may increase the risk of cardiometabolic conditions, but its association with incident dementia is unclear. The aim of this study was to assess the association between sleep regularity, that is, the day-to-day consistency in sleep-wake patterns and the risk of incident dementia and related brain MRI endophenotypes.
Methods
We used Cox proportional hazard models to investigate the relationships between sleep regularity and incident dementia in 88,094 UK Biobank participants. The sleep regularity index (SRI) was calculated as the probability of being in the same state (asleep/awake) at any 2 time points 24 hours apart, averaged over 7 days of accelerometry.
Results
The mean age of the sample was 62 years (SD = 8), 56% were women, and the median SRI was 60 (SD = 10). There were 480 cases of incident dementia over a median 7.2 years of follow-up. Following adjustments for demographic, clinical, and genetic confounders (APOE ε4), there was a nonlinear association between the SRI and dementia hazard (p [global test of spline term] < 0.001) with hazard ratios (HRs) following a U-shape pattern. HRs, relative to the median SRI, were 1.53 (95% CI 1.24–1.89) for participants with SRI at the 5th percentile (SRI = 41) and 1.16 (95% CI 0.89–1.50) for those with SRI at the 95th percentile (SRI = 71). In a subset with brain MRI (n = 15,263), gray matter and hippocampal volume tended to be lowest at the extremes of the SRI.
Discussion
Sleep regularity displayed a U-shaped association with risk of incident dementia. Irregular sleep may represent a novel dementia risk factor.
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© 2023 American Academy of Neurology.
Publication History
Received: April 10, 2023
Accepted: October 13, 2023
Published online: December 13, 2023
Published in print: January 23, 2024
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
Study Funding
M.P. Pase is supported by a National Health and Medical Research Council of Australia (GTN2009264, GTN1158384), National Institute on Aging (R01 AG062531), and Alzheimer's Association (2018-AARG-591358). M.G. Cavuoto and M.P. Pase are supported by a Dementia Australia Research Foundation award (Lucas' Papaw Remedies Project Grant). A.-A. Baril is funded by the Banting Fellowship Program (#454104). S.R. Yiallourou receives funding from the Alzheimer's Association (AARG-NTF-22-971405).
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Cited By
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- Sleep Timing, Sleep Timing Regularity, and Cognitive Performance in Women Entering Late Adulthood: The Study of Women's Health Across the Nation (SWAN), SLEEP, (2025).https://doi.org/10.1093/sleep/zsaf041
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We thank Dr. Kawada for commenting on our study where we identified a U-shaped relationship between sleep regularity and dementia risk; dementia risk was highest in persons with the most irregular sleep.1 We agree that sleep is highly complex, with different sleep metrics reflecting different aspects of sleep quality. Our two papers published in this issue highlight this point.1,2 In this study,1 sleep regularity was associated with brain volume and dementia and these associations were independent of sleep duration and WASO, with these models presented in our paper.
We did not exclude any dementia subtypes from our analysis. We studied all-cause dementia, which included dementia cases of several etiologies. We chose not to examine dementia subtypes separately given clinical diagnosis lacks precision and, most often, dementia is caused by multiple contributing pathologies. Further, when using UK Biobank healthcare datasets to identify dementia cases, the positive predictive values are much lower for dementia subtypes than all-cause dementia.3
As the reader suggests, there are many dementia risk factors and several could confound sleep-dementia associations. One strength of our paper was the robust consideration of confounding informed by a Directed Acyclic Graph (DAG). In total, our analyses adjusted for 23 covariates representing demographics, health/clinical, genetic, and social variables. Despite these comprehensive models, we cannot rule out residual confounding. Some of the factors suggested by the reader (e.g., immunity, metabolism) may not necessarily confound the sleep and dementia association, but perhaps serve as mediators, which we agree deserves further exploration.
We agree that the association between sleep and dementia could be bi-directional and this is something we have discussed here and elsewhere.1, 2, 4 Our comprehensive analysis represents an important step in understanding the relationship between irregular sleep and dementia with replication and extension in other cohorts needed.
Author disclosures are available upon request([email protected]).
Yiallourou et al. reported the effect of irregular sleep on the risk of dementia.1 The sleep regularity index (SRI) was calculated using an accelerometer, and adjusted hazard ratios (95% confidence intervals) of participants with SRI at the fifth and 95th percentiles against the median SRI for incident dementia were 1.53 (1.24–1.89) and 1.16 (0.89–1.50), respectively. Although SRI showed a U-shaped association with the risk of incident dementia, participants with regular sleep presented no significant association with incident dementia.
The same study group evaluated the association of sleep duration and its gradual change with amyloid, tau, neurodegeneration, and vascular neuroimaging markers of Alzheimer’s disease,2 and longer sleep duration was only associated with neurodegeneration and vascular neuroimaging markers. The authors observed an insignificant trend association of SRI with subsequent change in gray matter and hippocampal volumes. All-cause dementia was a clinical outcome,1 and types of dementia are excluded in the analysis. SRI and sleep duration present different characteristics in sleep, and both indicators might not directly present sleep quality. Some sleep indicators should be simultaneously used for the analysis to understand their relationship with dementia.
Sleep is an important lifestyle factor for maintaining good physical/mental health, and there may be a bidirectional association between sleep and dementia.3 Age-related factors, such as immunity and metabolism, sex differences, comorbidities, and some medications are closely related to the risk of dementia. Yiallourou et al. handled APOE ε4 as a genetic confounder, which is a key factor for the analysis. Overall, a comprehensive analysis is needed to understand the effect of irregular sleep on dementia.4,5
Author disclosures are available upon request([email protected]).