Association between serum total bilirubin and Alzheimer's disease: A bidirectional Mendelian randomization study

Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). As a potent antioxidant, serum bilirubin is decreased in AD and may be related to its pathogenesis, but the causal association between serum bilirubin and AD has not been reported. This was investigated in the present study by bidirectional two-sample Mendelian randomization (MR) analysis. Genetic instruments at the genome-wide significance level (P < 5 × 10^-8) were selected from the United Kingdom Biobank (n = 342,829). Summary-level AD data were obtained from a large-scale genome-wide association study (n = 63,926). Causal estimates were evaluated using the inverse variance weighted (IVW) approach and other five complementary methods. MR-Egger, IVW and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were used for sensitivity analyses. The results showed that there was no significant association between serum total bilirubin and AD (odds ratio=1.003, 95% confidence interval: 0.967-1.041, P = 0.865). Inverse MR revealed that serum total bilirubin was increased in AD (beta = 0.009, SE = 0.003, P = 0.010). These results indicate that serum total bilirubin is not causally associated with AD and cannot be used for screening or diagnosis, but can potentially serve as a biomarker of disease severity, and it needs further clinical studies.