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

Abstract

Background: The relationship between serum uric acid (UA) and Alzheimer's disease (AD) risk still remained ambiguous despite extensive attempts.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Alzheimer’s disease; Mendelian randomization; gout; uric acid.