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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.