Objective

To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer’s disease (AD).

Methods

We conducted bi-directional two-sample Mendelian randomisation analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (N=446,118), the Psychiatric Genomics Consortium (N=18,759), and the International Genomics of Alzheimer’s Project (N=63,926). We used the inverse variance weighted Mendelian randomisation method to estimate the causal effects, and the weighted median and MR-Egger for sensitivity analyses to test for pleiotropic effects.

Results

We 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 adjusting 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 a significant causal relationship between MDD and risk of AD.

Conclusion

We found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns in AD or evidence for a causal relationship between MDD and AD risk.