Causal Association between Circulating Metabolites and Dementia: A Mendelian Randomization Study

Abstract

The causal association of circulating metabolites with dementia remains uncertain. We assessed the causal association of circulating metabolites with dementia utilizing Mendelian randomization (MR) methods. We performed univariable MR analysis to evaluate the associations of 486 metabolites with dementia, Alzheimer's disease (AD), and vascular dementia (VaD) risk. For secondary validation, we replicated the analyses using an additional dataset with 123 metabolites. We observed 118 metabolites relevant to the risk of dementia, 59 of which were lipids, supporting the crucial role of lipids in dementia pathogenesis. After Bonferroni adjustment, we identified nine traits of HDL particles as potential causal mediators of dementia. Regarding dementia subtypes, protective effects were observed for epiandrosterone sulfate on AD (OR = 0.60, 95% CI: 0.48-0.75) and glycoproteins on VaD (OR = 0.89, 95% CI: 0.83-0.95). Bayesian model averaging MR (MR-BMA) analysis was further conducted to prioritize the predominant metabolites for dementia risk, which highlighted the mean diameter of HDL particles and the concentration of very large HDL particles as the predominant protective factors against dementia. Moreover, pathway analysis identified 17 significant and 2 shared metabolic pathways. These findings provide support for the identification of promising predictive biomarkers and therapeutic targets for dementia.

Keywords: Alzheimer’s disease; Mendelian randomization; dementia; metabolites; vascular dementia.

Figure 1

An overview of the study design. (a) The principles of the MR study. (b) Flowchart describing the sequence of analytical steps in this research. LD: linkage disequilibrium; IVs: instrumental variables; IVW: inverse-variance weighting; WM: weighted median.

Figure 2

Heatmap illustrating the causal estimates of circulating metabolites on dementia, AD and VaD. (A) Heatmap showing the univariable MR analysis result of 486 circulating metabolites in the primary analyses; (B) heatmap showing the univariable MR analysis result of 123 circulating metabolites in the secondary analyses. AD: Alzheimer’s disease; VaD: vascular dementia; IVW: inverse-variance weighting.

Figure 3

Forest plot of 11 causal features reaching the Bonferroni-adjusted threshold.

Figure 4

Forest plot of 46 potential risk predictors (p < 0.05) that remained robust in sensitivity analyses. 12-HETE, 12-hydroxyeicosatetraenoate; 7-Hoca, 7-alpha-hydroxy-3-oxo-4-cholestenoate.