The causal association between circulating metabolites and Alzheimer's disease: a systematic review and meta-analysis of Mendelian randomization studies

Abstract

Introduction/objective: Some Mendelian randomization (MR) studies have found that there may be a genetic causal relationship between circulating metabolites and Alzheimer 's disease (AD), but the strength of evidence and the direction of association are not always consistent. In this study, a systematic review and meta-analysis of all the literature using MR methods to study the causal relationship between metabolites and AD was conducted to enhance the robustness and correlation of predicting genetic causality.

Methods: We conducted a comprehensive review of Mendelian randomization (MR) studies which are within the timeframe of all years to 20 December 2023. Circulating metabolites were considered as the exposure factor, and AD served as the outcome. Two researchers, each with relevant professional backgrounds, independently evaluated study quality and extracted data from the selected studies. Meta-analysis was carried out using R Studio version 4.3.1.

Results: In total, 30 studies were included, with 13 selected for meta-analysis. The meta-analysis results revealed that genetically predicted high levels of some metabolites may be associated with a reduced risk of AD. (HDL-C: OR = 0.90, 95% CI 0.83-0.97, p = 0.004; Testosterone: OR = 0.93, 95% CI 0.90-0.97, p = 0.001; Male hormones _{exclude testosterone}: OR = 0.85, 95% CI 0.75-0.96, p = 0.007; Glutamine: OR = 0.85, 95% CI 0.81-0.89, p < 0.001) Meanwhile, genetically predicted high LDL-C levels are associated with an increased risk of AD. (LDL-C: OR = 1.52, 95% CI 1.15-2.00, p = 0.003). There is not enough evidence to prove that there is a genetic causal relationship between diabetes and AD. (OR = 1.02, 95% CI 1.00-1.03, p = 0.12).

Keywords: Alzheimer’s disease; Circulating metabolites; Mendelian randomization.

Fig. 1

Preferred reporting items of systematic review and meta-analyses flow diagram

Fig. 2

The results of a meta-analysis of the causal relationship between LDL-C, HDL-C and AD. a Forest plot of studies that evaluated the causal effect between LDL-C and all AD outcomes using values obtained by the IVW MR method. b Forest plot of studies that evaluated the causal effect between LDL-C and all AD outcomes using values obtained by the Weighted median MR method. c Forest plot of studies that evaluated the causal effect between HDL-C and all AD outcomes using values obtained by the IVW MR method. dForest plot of studies that evaluated the causal effect between HDL-C and all AD outcomes using values obtained by the Weighted median MR method

Fig. 3

The results of a meta-analysis of the causal relationship between Male hormones, Testosterone, and AD. a Forest plot of studies that evaluated the causal effect between testosterone and all AD outcomes using values obtained by the IVW MR method. b Forest plot of studies that evaluated the causal effect between testosterone and Female AD outcomes using values obtained by the IVW MR method. c Forest plot of studies that evaluated the causal effect between testosterone and Male AD outcomes using values obtained by the IVW MR method. d Forest plot of studies that evaluated the causal effect between male hormones (exclude testosterone) and AD outcomes using values obtained by the IVW MR method

Fig. 4

The meta-analysis results of the causal relationship between Glutamine and AD. a Forest plot of studies that evaluated the causal effect between glutamine and AD outcomes using values obtained by the IVW MR method. b Forest plot of studies that evaluated the causal effect between diabetes and AD outcomes using values obtained by the IVW MR method