Journal of Shandong University (Health Sciences) ›› 2026, Vol. 64 ›› Issue (9): 26-35.doi: 10.6040/j.issn.1671-7554.0.2025.1202

• Clinical Medicine • Previous Articles    

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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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

CLC Number: 

  • R749.1+6
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