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Sleep Characteristics and Risk of Stroke and Dementia An Observational and Mendelian Randomization Study

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Guo, Chutian 
Harshfield, Eric L 
Markus, Hugh S 

Abstract

Background and Objectives: Sleep disturbances are implicated as risk factors for both stroke and dementia. However, whether these associations are causal and whether treatment of sleep disorders could reduce stroke and dementia risk remains uncertain. We aimed to evaluate associations and ascertain causal relationships between sleep characteristics and stroke/dementia risk and MRI markers of SVD.

Methods: We used datasets from a multicentre population-based study, and summary statistics from genome-wide association studies (GWAS) of sleep characteristics and outcomes. We analysed 502,383 UK Biobank participants with self-reported sleep measurements, including sleep duration, insomnia, chronotype, napping, daytime dozing, and snoring. In observational analyses, the primary outcomes were incident stroke, dementia, and their subtypes, alongside SVD markers. Hazard ratios (HR) and odds ratios (OR) were adjusted for age, sex, and ethnicity, and additional vascular risk factors. In MR analyses, ORs or risk ratios are reported for the association of each genetic score with clinical or MRI endpoints.

Results: Among 502,383 participants (mean [SD] age, 56.5 [8.1] years; 54.4% female), there were 7,668 cases of all-cause dementia and 10,334 strokes. In longitudinal analyses, after controlling for cardiovascular risk factors, participants with insomnia, daytime napping and dozing were associated with increased risk of any stroke (HR=1.05, 95% CI=1.01-1.11, p=8.53x10-3; HR=1.09, 95% CI=1.05-1.14, p=3.20x10-5; HR=1.19, 95% CI=1.08-1.32, p=4.89x10-4, respectively). Almost all sleep measures were associated with dementia risk (all p<0.001 except insomnia). Cross-sectional analyses identified associations between napping, snoring, and MRI markers of SVD (all p<0.001). MR analyses supported a causal link between genetically predicted insomnia and increased stroke risk (OR=1.31, 95%CI=1.13-1.51, p=0.00072), but not with dementia or SVD markers.

Discussion: We found multiple sleep measures predicted future risk of stroke and dementia, but these associations were attenuated after controlling for cardiovascular risk factors and were absent in MR analyses for Alzheimer’s disease. This suggests possible confounding or reverse causation, implying caution before proposing sleep disorder modifications for dementia treatment.

Description

Keywords

Female, Humans, Middle Aged, Male, Sleep Initiation and Maintenance Disorders, Cross-Sectional Studies, Genome-Wide Association Study, Mendelian Randomization Analysis, Snoring, Stroke, Sleep, Alzheimer Disease

Journal Title

Neurology

Conference Name

Journal ISSN

0028-3878
1526-632X

Volume Title

Publisher

Lippincott, Williams & Wilkins
Sponsorship
British Heart Foundation (RG/F/22/110052)
Alzheimer's Society (573 (AS-RF-21-017))
British Heart Foundation (RE/18/1/34212)
This research was funded by a British Heart Foundation program grant (RG/F/22/110052). Infrastructural support was provided by the Cambridge British Heart Foundation Centre of Research Excellence (RE/18/1/34212) and Cambridge University Hospitals NIHR Biomedical Research Centre (BRC-1215-20014). ELH is funded by the Alzheimer’s Society (AS-RF-21-017). The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS, or UK Department of Health and Social Care.

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