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

Article type: Research Article

Authors: Ou, Ya-Nan^a | Zhao, Bing^a | Fu, Yan^a | Sheng, Ze-Hu^a | Gao, Pei-Yang^a | Tan, Lan^{a; *} | Yu, Jin-Tai^{b; *}

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China | [b] Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China

Correspondence: [*] Correspondence to: Prof. Jin-Tai Yu, Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12th WulumuqiZhong Road, Shanghai 200040, China. Tel.: +86 21 52888160; Fax: +86 21 62483421; E-mail: [email protected]. and Prof. Lan Tan, Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China. E-mail: [email protected].

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, gout, Mendelian randomization, uric acid

DOI: 10.3233/JAD-220649

Journal: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1063-1073, 2022