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山东大学学报 (医学版) ›› 2026, Vol. 64 ›› Issue (9): 26-35.doi: 10.6040/j.issn.1671-7554.0.2025.1202

• 临床医学 • 上一篇    

血浆与尿液代谢物对阿尔茨海默病的因果效应:全代谢组孟德尔随机化研究

彭强1,2,张雪芹2,文俊1,2,王凯2,张晓娟2,刘世平3   

  1. 1.川北医学院临床医学院, 四川 南充 637100;2.广元市精神卫生中心(川北医学院附属广元市第三人民医院), 四川 广元 628001;3.川北医学院附属医院, 四川 南充 637000
  • 发布日期:2026-09-09
  • 通讯作者: 刘世平. E-mail:liusp@163.com
  • 基金资助:
    四川省卫生健康委员会医学科技项目(25QNMP064)

Causal effects of plasma and urinary metabolites on Alzheimers disease: a metabolome-wide Mendelian randomization study

PENG Qiang1,2, ZHANG Xueqin2, WEN Jun1,2, WANG Kai2, ZHANG Xiaojuan2, LIU Shiping3   

  1. 1. School of Clinical Medicine, North Sichuan Medical College, Nanchong 637100, Sichuan, China;
    2.Guangyuan Mental Health Centre(Affiliated Hospital of North Sichuan Medical College, Guangyuan Third Peoples Hospital), Guangyuan 628001, Sichuan, China;
    3. Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan, China
  • Published:2026-09-09

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摘要： 目的 基于孟德尔随机化(Mendelian randomization, MR)方法与代谢组学技术,筛选阿尔茨海默病(Alzheimers disease, AD)相关的代谢标志物,探索其相关风险因素,并揭示代谢物在其中的中介机制。 方法 采用双样本MR评估690种血浆代谢物和211种尿液代谢物与AD之间的因果关联,通过MetOrigin平台对潜在代谢标志物进行功能富集分析,利用DrugBank进行成药性评价;进一步分析可改变风险因素与候选代谢物之间的因果关系,并采用两步法MR分析代谢物的中介效应。 结果 初步筛选出13种血浆代谢物和7种尿液代谢物与AD存在因果关系(P<0.05),功能富集分析确定5条相关的代谢途径(P<0.05),成药性评价显示2种代谢物可作为潜在治疗靶点。此外,确定5个与AD相关的可改变风险因素(P<0.05),中介分析确认2种代谢物在风险因素介导AD中发挥中介作用。 结论 13种血浆代谢物和7种尿液代谢物与AD存在因果关联,其中S-腺苷同型半胱氨酸和乳糖可作为潜在治疗靶点,硫酸表雄酮和1-棕榈酰-2-油酰-GPI分别在抑郁症状和帕金森病与AD的关联中发挥中介作用。

关键词: 阿尔茨海默病, 孟德尔随机化, 代谢物, 因果效应, 风险因素, 中介机制

Abstract: Objective To identify metabolic biomarkers causally associated with Alzheimers disease(AD)using Mendelian randomization(MR)and metabolomics, explore related risk factors, and elucidate the mediating role of metabolites. Methods Two-sample MR was used to evaluate the causal associations of 690 plasma metabolites and 211 urinary metabolites with AD. Functional enrichment analysis of potential metabolic markers was performed using Met Origin, and druggability assessment was conducted via Drug Bank. MR analyses were further performed to identify modifiable risk factors for AD and their causal relationships with candidate metabolites, followed by two-step MR to assess mediating effects of metabolites. Results Thirteen plasma metabolites and seven urinary metabolites showed significant causal associations with AD(P<0.05). Functional enrichment analysis identified five significantly enriched metabolic pathways(P<0.05). Druggability assessment indicated two metabolites as potential therapeutic targets. Additionally, five modifiable risk factors for AD were identified(P<0.05), and mediation analysis confirmed the mediating roles of two metabolites in risk factor-induced AD. Conclusion Thirteen plasma metabolites and seven urinary metabolites were causally associated with AD. Among them, S-adenosylhomocysteine and lactose emerged as potential therapeutic targets, while epiandrosterone sulfate and 1-palmitoyl-2-oleoyl-GPI mediated the effects of depressive symptoms and Parkinsons disease on AD, respectively.

Key words: Alzheimers disease, Mendelian randomization, Metabolites, Causal association, Risk factors, Mediation

中图分类号: 

  • R749.1+6
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