There are currently no disease modifying treatments for Alzheimers Disease (AD). Epidemiological studies have highlighted blood metabolites as potential biomarkers, but possible confounding and reverse causation prevent causal conclusions. Here, we investigated whether nineteen metabolites previously associated with midlife cognitive function, are on the causal pathway to AD. Summary statistics from the largest Genome-Wide Association Studies (GWAS) for AD and for metabolites were used to perform bi-directional univariable Mendelian Randomisation (MR). Bayesian model averaging MR (MR-BMA) was additionally performed to address high correlation between metabolites and to identify metabolite combinations which may be on the AD causal pathway. Univariable MR indicated three Extra-Large High-Density Lipoproteins (XL.HDL) to be on the causal pathway to AD: Free Cholesterol (XL.HDL.FC: OR=0.86, 95% CI=0.78-0.94), Total Lipids (XL.HDL.L: OR=0.88, 95% CI=0.80-0.97), and Phospholipids (XL.HDL.PL: OR=0.87, 95% CI=0.81-0.97); significant at an adjusted threshold of p<0.009. MR-BMA corroborated XL.HDL.FC to be amongst the top three causal metabolites, additionally to Total Cholesterol in XL.HDL (XL.HDL.C) and Glycoprotein Acetyls (GP) (posterior probabilities=0.112, 0.113, 0.287 respectively). Both XL.HDL.C and GP also demonstrated suggestive evidence of univariable causal associations (XL.HDL.C:OR=0.88, 95% CI=0.79-0.99; GP:OR=1.2, 95% CI=1.05-1.38); significant at the 5% level. This study offers insight into the causal relationship between metabolites previously demonstrating association with mid-life cognition, and AD. It highlights GP in addition to several XL.HDLs as causal candidates which warrant further investigation. As the pathological changes underpinning AD are thought to develop decades prior to symptom onset, progressing these findings could hold special value in informing future risk reduction strategies.

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解读血液代谢产物与阿尔茨海默氏病之间的因果关系：孟德尔随机研究

当前没有针对阿尔茨海默氏病（AD）的疾病改良疗法。流行病学研究强调血液代谢物是潜在的生物标志物，但可能的混淆和反向因果关系阻止了因果关系结论。在这里，我们调查了以前与中年认知功能相关的19种代谢物是否在AD的病因途径上。来自最大的全基因组关联研究（GWAS）的AD和代谢物的汇总统计数据用于执行双向单变量孟德尔随机化（MR）。贝叶斯模型平均MR（MR-BMA）额外执行以解决代谢物之间的高度相关性，并确定可能在AD因果路径上的代谢物组合。单变量MR表示三种超高密度脂蛋白（XL。HDL）可能是AD的病因途径：游离胆固醇（XL.HDL.FC：OR = 0.86，95％CI = 0.78-0.94），总脂质（XL.HDL.L：OR = 0.88，95％CI = 0.80-0.97）和磷脂（XL.HDL.PL：OR = 0.87，95％CI = 0.81-0.97）; 在调整的阈值p <0.009时显着。MR-BMA证实XL.HDL.FC属于前三位因果代谢产物，此外还证实XL.HDL（XL.HDL.C）和糖蛋白乙酰基（GP）中的总胆固醇（后验概率分别为0.112、0.113、0.287） 。XL.HDL.C和GP均显示出单变量因果关联的暗示证据（XL.HDL.C：OR = 0.88，95％CI = 0.79-0.99； GP：OR = 1.2，95％CI = 1.05-1.38）；在5％的水平显着。这项研究提供了以前证明与中年认知相关的代谢产物与AD之间因果关系的见解。除几个XL外，它还突出显示GP。HDL是因果关系候选者，值得进一步调查。由于支持AD的病理学改变在症状发作之前已经发展了几十年，因此进展这些发现可能对告知未来降低风险的策略具有特殊价值。