[Plasma metabolites mediates the causal effect of inflammatory proteins on Alzheimer's disease: a Mendelian...

To investigate the causal relationship between inflammatory proteins and Alzheimer's disease (AD) and the mediating role of plasma metabolites therein.

Using Mendelian mandomization (MR) methods and publicly available genome-wide association study (GWAS) data, we selected 91 single nucleotide polymorphisms (SNPs) that were strongly linked to inflammatory proteins without reverse causality with AD as the outcome. A bidirectional two-sample MR analysis was performed. Inflammatory proteins with causal links to AD were identified via inverse variance weighted (IVW) analysis. A mediation MR analysis was then performed using 1400 plasma metabolites to assess their mediating role in this causal pathway.

The preliminary bidirectional MR analysis identified 3 inflammatory proteins that had a potential positive causal association with AD without reverse causality: Axin-1, C-X-C motif chemokine ligand 11 (CXCL11), and interleukin-12β (IL-12β). Elevated levels of Axin-1 were positively causally associated with AD risk (OR=1.082, 95% CI: 1.009-1.159; P=0.026), while CXCL11 (OR=0.951, 95% CI: 0.914-0.990; P=0.026) and IL-12β (OR=0.959, 95% CI: 0.926-0.994; P=0.026) were negatively causally associated with AD risk. Sensitivity analyses indicated that these causal effects exhibited no heterogeneity or pleiotropy. In the mediation analysis, 18 plasma metabolites with causal links to AD were identified, among which 3 plasma metabolites exhibited mediating effects in the inflammatory protein-AD causal relationship. Methyl-4-hydroxybenzoate sulfate partially mediated the effect between Axin-1 and AD (20.10%). Pregnenetriol sulfate partially mediated the effect between CXCL11 and AD (18.20%). The ratio of spermidine to ornithine played an important mediating role between IL-12β and AD, with a mediating effect of 43.40%.

This study reveals how specific inflammatory proteins influence AD risk via plasma metabolites and provides genetic evidence for inflammatory-metabolic interactions in AD to facilitate the identification of potential biomarkers and targets for early detection and intervention of AD.