• Jian Huang, Verena Zuber, Paul M Matthews, Paul Elliott, Joanna Tzoulaki, and Abbas Dehghan.
• From the MRC Centre for Environment and Health (J.H., V.Z., P.E., J.T., A.D.), Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Campus, Imperial College London, Norfolk Place; UK Dementia Research Institute at Imperial College London (J.H., P.M.M., J.T., A.D.); Imperial College NIHR Biomedical Research Centre (J.H., P.E.); Department of Brain Sciences (P.M.M., P.E.), Faculty of Medicine, Imperial College London; Health Data Research UK-London; and Department of Hygiene and Epidemiology (P.E., J.T.), University of Ioannina Medical School, Greece.
• Neurology. 2020 Oct 6; 95 (14): e1963-e1970.

ObjectiveTo explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD).MethodsWe conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). We used the inverse variance-weighted Mendelian randomization method to estimate causal effects and weighted median and Mendelian randomization-Egger for sensitivity analyses to test for pleiotropic effects.ResultsWe found that higher risk of AD was significantly associated with being a "morning person" (odds ratio [OR] 1.01, p = 0.001), shorter sleep duration (self-reported: β = -0.006, p = 1.9 × 10-4; accelerometer based: β = -0.015, p = 6.9 × 10-5), less likely to report long sleep (β = -0.003, p = 7.3 × 10-7), earlier timing of the least active 5 hours (β = -0.024, p = 1.7 × 10-13), and a smaller number of sleep episodes (β = -0.025, p = 5.7 × 10-14) after adjustment for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR 0.99, p = 7 × 10-13). However, we did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD.ConclusionWe found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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