Observational studies have shown that gut microbiota-dependent metabolites are associated with the risk of Alzheimer's disease (AD). However, whether such association reflects a causality remains unclear. We conducted a bidirectional Mendelian randomization analysis to examine the causal relationships between gut microbiota-dependent metabolites trimethylamine N-oxide (TMAO) or its predecessors and AD. We observed that genetically predicted TMAO (odds ratio: 0.99, 95% confidence interval: 0.89 to 1.09 per 10 units, p = 0.775) or its predecessors including betaine (1.06, 1.00 to 1.12 per 10 units, p = 0.056), carnitine (1.05, 0.98 to 1.12 per 10 units, p = 0.178), and choline (1.01, 0.92 to 1.10 per 10 units, p = 0.905) were not associated with the risk of AD. Our Mendelian randomization estimates from AD to metabolites showed that genetically predicted higher risk of AD was also not causally associated with TMAO, betaine, carnitine, and choline levels. Our findings support that gut microbiota-dependent metabolites TMAO or its predecessors do not play causal roles in the development of AD.

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肠道代谢物与阿尔茨海默病之间的因果关系：双向孟德尔随机化研究

观察性研究表明，肠道微生物群依赖的代谢物与阿尔茨海默病 (AD) 的风险有关。然而，这种关联是否反映了因果关系尚不清楚。我们进行了双向孟德尔随机化分析，以检查依赖肠道微生物群的代谢物三甲胺 N-氧化物 (TMAO) 或其前身与 AD 之间的因果关系。我们观察到基因预测的 TMAO（优势比：0.99，95% 置信区间：0.89 至 1.09 每 10 个单位，p = 0.775）或其前身，包括甜菜碱（1.06、1.00 至 1.12 每 10 个单位，p = 0.056 (p = 0.056)、肉碱） 1.05、0.98 至 1.12 每 10 单位，p = 0.178）和胆碱（每 10 单位 1.01、0.92 至 1.10，p = 0.905）与 AD 风险无关。我们从 AD 到代谢物的孟德尔随机估计表明，遗传预测的 AD 较高风险也与 TMAO、甜菜碱、肉碱和胆碱水平没有因果关系。我们的研究结果支持肠道微生物群依赖性代谢物 TMAO 或其前身在 AD 的发展中不发挥因果作用。