Association between Human Blood Metabolome and the Risk of Alzheimer's Disease

Objective Alzheimer's disease (AD) is the most common degenerative neurological disorder with limited therapeutic options. Therefore, it is particularly important to explore the potential biomarkers implicated in the occurrence and progression of AD prior to clinical testing. Methods We selected 119 unique blood metabolites from 3 metabolome genome‐wide association studies (GWASs) with 147,827 European participants. Summary data about AD were obtained from a GWAS meta‐analysis with 63,926 European individuals from the International Genomics of Alzheimer's Project. MR analyses were performed to assess the associations of blood metabolites with AD, and a phenome‐wide MR analysis was further applied to ascertain the potential on‐target side effects of metabolite interventions. Results Four metabolites were identified as causal mediators for AD, including epiandrosterone sulfate (odds ratio [OR] per SD increase: 0.60; 95% confidence interval [CI]: 0.51–0.71; p = 6.14 × 10−9), 5alpha‐androstan‐3beta‐17beta‐diol disulfate (OR per SD increase: 0.69; 95% CI: 0.57–0.84; p = 1.98 × 10−4), sphingomyelin (OR per SD increase: 2.53; 95% CI: 1.78–3.59; p = 2.10 × 10−7), and glutamine (OR per SD increase: 0.83; 95% CI: 0.77–0.89; p = 2.09 × 10−6). Phenome‐wide MR analysis showed that epiandrosterone sulfate, 5alpha‐androstan‐3beta‐17beta‐diol disulfate and sphingomyelin mediated the risk of multiple diseases, and glutamine had beneficial effects on the risk of 4 diseases. Interpretation Genetically predicted increased epiandrosterone sulfate, 5alpha‐androstan‐3beta‐17beta‐diol disulfate, and glutamine might be associated with a decreased risk of AD, while sphingomyelin was associated with an increased risk. Side‐effect profiles were characterized to help inform drug target prioritization, and glutamine might be a promising target for the prevention and treatment of AD with no predicted detrimental side effects. ANN NEUROL 2022;92:756–767