Abstract
BACKGROUND: Alzheimer's disease (AD) is the most frequently occurring type of dementia. Concurrently, inadequate sleep has been recognized as a public health epidemic. Notably, genetic and environmental factors are now considered contributors to AD progression. OBJECTIVE: To assess the association between sleep duration, genetic susceptibility, and AD. METHODS AND RESULTS: Based on 483,507 participants from the UK Biobank (UKB) with an average follow-up of 11.3 years, there was a non-linear relationship between AD incidence and sleep duration (P for non-linear < 0.001) by restricted cubic splines (RCS). Sleep duration was categorized into short sleep duration (< 6 h/night), normal sleep duration (6-9 h/night), and long sleep duration (> 9 h/night). No statistically significant interaction was identified between sleep duration and the AD-GRS (Alzheimer's disease genetic risk score, P for interaction = 0.45) using Cox proportional risk model. Compared with the participants who had a low AD-GRS and normal sleep duration, there was associated with a higher risk of AD in participants with a low AD-GRS and long sleep duration (HR = 3.4806; 95% CI 2.0011-6.054, p < 0.001), participants with an intermediate AD-GRS and long sleep duration (HR = 2.0485; 95% CI 1.3491-3.1105, p < 0.001), participants with a high AD-GRS and normal sleep duration (HR = 1.9272; 95% CI 1.5361-2.4176, p < 0.001), and participants with a high AD-GRS and long sleep duration (HR = 5.4548; 95% CI 3.1367-9.4863, p < 0.001).In addition, there was no causal association between AD and sleep duration using Two Sample Mendelian randomization (MR). CONCLUSION: In the UKB population, though there was no causal association between AD and sleep duration analyzed using Two Sample MR, long sleep duration (> 9 h/night) was significantly associated with a higher risk of AD, regardless of high, intermediate or low AD-GRS. Prolonged sleep duration may be one of the clinical predictors of a higher risk of AD.