Investigating Causal Relations Between Risk Tolerance, Risky Behaviors, and Alzheimer’s Disease: A Bidirectional Two-Sample Mendelian Randomization Study

BACKGROUND: Several studies have shown risky behaviors and risk tolerance are associated with Alzheimer's disease. However, the underlying causality remains unclear. Risky behavior and risk tolerance may induce the onset of Alzheimer's disease, and/or vulnerability to Alzheimer's disease may result in more risky behaviors. OBJECTIVE: To examine bidirectional relationships between risky behavior, risk tolerance, and Alzheimer's disease using Mendelian randomization method for assessing potential causal inference. METHODS: This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with risky behaviors and risk tolerance (n = 370, 771- 939, 908), and Alzheimer's disease (n = 71, 880 - 37, 613) as genetic instruments from large meta-analyses of genome-wide association studies. RESULTS: Our results support a strong protective casual effect of risk-taking tendency on AD (odds ratio [OR] = 0.79; 95% CI, 0.67- 0.94, p = 0.007). There was weak statistically significant relationship between number of sexual partners and AD (OR = 0.50, 95% CI, 0.27- 0.93, p = 0.04), and between family history of AD and automobile speeding propensity (OR = 1.018, 95% CI, 1.005 to 1.031; p = 0.007). Contrary to expectations, there was no statistically significant causal effect of AD on risk-taking tendency (β= 0.015, 95% CI, - 0.005 to 0.04; p = 0.14). CONCLUSION: Under Mendelian randomization assumptions, our results suggest a protective relationship between risk-taking tendency and the risk of AD. This finding may provide valuable insights into Alzheimer's disease pathogenesis and the development of preventive strategies.