The Association of Serum Uric Acid Level, Gout, and Alzheimer's Disease: A Bidirectional Mendelian Randomization Study.

Abstract

The relationship between serum uric acid (UA) and Alzheimer's disease (AD) risk still remained ambiguous despite extensive attempts. Via the two-sample Mendelian randomization (MR) design, we aimed to examine the bidirectional causal relationships of serum UA, gout, and the risk of AD. Genetic variants of UA, gout, and AD were extracted from published genome-wide association summary statistics. The inverse-variance weighted (IVW, the primary method), and several sensitivity methods (MR-Egger, weighted median, and weighted mode) were used to calculate the effect estimates. Egger regression, MR-PRESSO and leave-one-SNP-out analysis were performed to identify potential violations. Genetic proxies for serum UA concentration [odds ratio (ORIVW) = 1.09, 95% confidence interval (CI) = 1.01-1.19, p = 0.031] were related with an increased risk of AD using 25 single nucleotide polymorphisms (SNPs). This causal effect was confirmed by sensitivity analyses including MR-Egger (1.22, 1.06-1.42, p = 0.014), weighted median (1.18, 1.05-1.33, p = 0.006), and weighted mode (1.20, 1.07-1.35, p = 0.005) methods. No evidence of notable directional pleiotropy and heterogeneity were identified (p > 0.05). Three SNPs (rs2078267, rs2231142, and rs11722228) significantly drove the observed causal effects. Supportive causal effect of genetically determined gout on AD risk was demonstrated using two SNPs (ORIVW = 1.05, 95% CI = 1.00-1.11, p = 0.057). No reverse causal effects of AD on serum UA levels and gout risk were found. The findings revealed a causal relationship between elevated serum UA level and AD risk. However, further research is still warranted to investigate whether serum UA could be a reliable biomarker and therapeutic target for AD.