Ahmad Shahzad, Wu Tong, Arnold Matthias, Hankemeier Thomas, Ghanbari Mohsen, Roshchupkin Gennady, Uitterlinden André G, Neitzel Julia, Kraaij Robert, Van Duijn Cornelia M, Arfan Ikram M, Kaddurah-Daouk Rima, Kastenmüller Gabi
Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
medRxiv. 2024 Dec 16:2024.12.16.24317793. doi: 10.1101/2024.12.16.24317793.
Increasing evidence suggests the involvement of metabolic alterations in neurological disorders, including Alzheimer's disease (AD), and highlights the significance of the peripheral metabolome, influenced by genetic factors and modifiable environmental exposures, for brain health. In this study, we examined 1,387 metabolites in plasma samples from 1,082 dementia-free middle-aged participants of the population-based Rotterdam Study. We assessed the relation of metabolites with general cognition (G-factor) and magnetic resonance imaging (MRI) markers using linear regression and estimated the variance of these metabolites explained by genes, gut microbiome, lifestyle factors, common clinical comorbidities, and medication using gradient boosting decision tree analysis. Twenty-one metabolites and one metabolite were significantly associated with total brain volume and total white matter lesions, respectively. Fourteen metabolites showed significant associations with G-factor, with ergothioneine exhibiting the largest effect (adjusted mean difference = 0.122, = 4.65×10). Associations for nine of the 14 metabolites were replicated in an independent, older cohort. The metabolite signature of incident AD in the replication cohort resembled that of cognition in the discovery cohort, emphasizing the potential relevance of the identified metabolites to disease pathogenesis. Lifestyle, clinical variables, and medication were most important in determining these metabolites' blood levels, with lifestyle, explaining up to 28.6% of the variance. Smoking was associated with ten metabolites linked to G-factor, while diabetes and antidiabetic medication were associated with 13 metabolites linked to MRI markers, including N-lactoyltyrosine. Antacid medication strongly affected ergothioneine levels. Mediation analysis revealed that lower ergothioneine levels may partially mediate negative effects of antacids on cognition (31.5%). Gut microbial factors were more important for the blood levels of metabolites that were more strongly associated with cognition and incident AD in the older replication cohort (beta-cryptoxanthin, imidazole propionate), suggesting they may be involved later in the disease process. The detailed results on how multiple modifiable factors affect blood levels of cognition- and brain imaging-related metabolites in dementia-free participants may help identify new AD prevention strategies.
越来越多的证据表明，代谢改变与包括阿尔茨海默病（AD）在内的神经疾病有关，并凸显了受遗传因素和可改变的环境暴露影响的外周代谢组对大脑健康的重要性。在本研究中，我们检测了基于人群的鹿特丹研究中1082名无痴呆中年参与者血浆样本中的1387种代谢物。我们使用线性回归评估了代谢物与一般认知（G因子）和磁共振成像（MRI）标志物的关系，并使用梯度提升决策树分析估计了由基因、肠道微生物群、生活方式因素、常见临床合并症和药物解释的这些代谢物的方差。分别有21种代谢物和1种代谢物与全脑体积和总白质病变显著相关。14种代谢物与G因子显著相关，其中麦角硫因的影响最大（调整后平均差异=0.122， =4.65×10）。在一个独立的老年队列中重复了14种代谢物中9种的关联。复制队列中偶发AD的代谢物特征与发现队列中的认知特征相似，强调了所鉴定的代谢物与疾病发病机制的潜在相关性。生活方式、临床变量和药物在决定这些代谢物的血液水平方面最为重要，其中生活方式解释了高达28.6%的方差。吸烟与10种与G因子相关的代谢物有关，而糖尿病和抗糖尿病药物与13种与MRI标志物相关的代谢物有关，包括N-乳酰酪氨酸。抗酸药物强烈影响麦角硫因水平。中介分析显示，较低的麦角硫因水平可能部分介导抗酸剂对认知的负面影响（31.5%）。肠道微生物因素对老年复制队列中与认知和偶发AD更密切相关的代谢物的血液水平更为重要（β-隐黄质、咪唑丙酸），表明它们可能在疾病过程的后期起作用。关于多种可改变因素如何影响无痴呆参与者中与认知和脑成像相关的代谢物血液水平的详细结果，可能有助于确定新的AD预防策略。
