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    Unbiased metabolome screen links serum urate to risk of Alzheimer's disease
    (Elsevier Science Inc, 2022) Sanli, Beyazit Abdurrahman; Whittaker, Katherine J.; Motsi, Gamuchirai K.; Shen, Emery; Julian, Thomas H.; Cooper-Knock, Johnathan
    Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease caused by a combination of genetic and environmental risk factors. The serum metabolome refers to a set of small-molecules which are an important determinant of cellular health. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 376 metabolites which were population matched with 2 GWAS studies of AD. For each metabolite we performed 2-sample MR (2SMR) using an inverse variance weighted (IVW) estimate for significance testing. After Bonferroni multiple testing correction one metabo-lite was causally linked to AD in both GWAS: serum urate. This result was supported by robust 2SMR measures and sensitivity analyses. We applied 2SMR to test for a causal relationship between serum urate and other neurodegenerative diseases: Parkinson disease (PD) and Amyotrophic lateral sclerosis (ALS). In ALS but not PD we identified a nominally significant link between serum urate and disease-risk, although in this case increased serum urate was protective. We conclude that serum urate is a modulator of risk for neurodegeneration. Our work has implications for the design of preventative interventions.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license( http://creativecommons.org/licenses/by/4.0/ )