Causal Associations of Sleep Apnea With Alzheimer Disease and Cardiovascular Disease: A Bidirectional Mendelian Randomization Analysis

Abstract

Background: Sleep apnea (SA) has been linked to an increased risk of dementia in numerous observational studies; whether this is driven by neurodegenerative, vascular, or other mechanisms is not clear. We sought to examine the bidirectional causal relationships between SA, Alzheimer disease (AD), coronary artery disease (CAD), and ischemic stroke using Mendelian randomization.

Methods and results: Using summary statistics from 4 recent, large genome-wide association studies of SA (n=523 366), AD (n=94 437), CAD (n=1 165 690), and stroke (n=1 308 460), we conducted bidirectional 2-sample Mendelian randomization analyses. Our primary analytic method was fixed-effects inverse variance-weighted (IVW) Mendelian randomization; diagnostics tests and sensitivity analyses were conducted to verify the robustness of the results. We identified a significant causal effect of SA on the risk of CAD (odds ratio [OR_IVW]=1.35 per log-odds increase in SA liability [95% CI=1.25-1.47]) and stroke (OR_IVW=1.13 [95% CI=1.01-1.25]). These associations were somewhat attenuated after excluding single-nucleotide polymorphisms associated with body mass index (OR_IVW=1.26 [95% CI=1.15-1.39] for CAD risk; OR_IVW=1.08 [95% CI=0.96-1.22] for stroke risk). SA was not causally associated with a higher risk of AD (OR_IVW=1.14 [95% CI=0.91-1.43]). We did not find causal effects of AD, CAD, or stroke on risk of SA.

Conclusions: These results suggest that SA increased the risk of CAD, and the identified causal association with stroke risk may be confounded by body mass index. Moreover, no causal effect of SA on AD risk was found. Future studies are warranted to investigate cardiovascular pathways between sleep disorders, including SA, and dementia.

Keywords: Alzheimer disease; Mendelian randomization; cardiovascular diseases; causal inference; coronary artery disease; sleep apnea; stroke.

Figure 1. Scatter and funnel plots for each relationship between sleep apnea and the different outcomes (Alzheimer disease, coronary artery disease, and stroke).

A, C, and E, Scatterplots () show the sleep apnea variant effect size against the outcome variant effect size and corresponding SEs. B, D, and F, Funnel plots show the Mendelian randomization (MR) causal estimates for each variant against its precision, with asymmetry in the plot indicating potential violations of the assumptions of MR. Regression lines show the corresponding causal estimates: fixed‐effect inverse‐weighted (green line) meta‐analysis; MR‐Egger regression (orange line); weighted median‐based estimator (purple line); and weighted mode‐based estimator (blue line). IV indicates instrumental variable; and SNP, single‐nucleotide polymorphism.

Figure 2. Scatter and funnel plots for each relationship in the bidirectional analysis between the different exposures (Alzheimer disease, coronary artery disease, and stroke) and sleep apnea.

A, C, and E, Scatterplots show the exposure variant effect size against the sleep apnea variant effect size and corresponding SEs. B, D, and F, Funnel plots show the Mendelian randomization (MR) causal estimates for each variant against its precision, with asymmetry in the plot indicating potential violations of the assumptions of MR. Regression lines show the corresponding causal estimates: fixed‐effect inverse‐weighted (green line) meta‐analysis; MR‐Egger regression (orange line); weighted median‐based estimator (purple line); and weighted mode‐based estimator (blue line). IV indicates instrumental variable; and SNP, single‐nucleotide polymorphism.