# Association of the Lipidome With Alzheimer's Disease and the Mediated Effect of Metabolites: A Two‐Step Mendelian Randomization Study

## TL;DR

This study uses genetic data to show how certain lipids reduce Alzheimer's disease risk by lowering betaine levels.

## Contribution

The study identifies specific lipid species that mediate reduced Alzheimer's risk through betaine level modulation using Mendelian randomization.

## Key findings

- Phosphatidylcholine (15:0_18:2) and phosphatidylethanolamine (18:0_18:2) reduce AD risk by lowering betaine levels.
- MR analysis revealed a mediated effect with significant proportions (18.30% and 14.60%) for these lipids.
- Results were robust with no evidence of horizontal pleiotropy and passed sensitivity analysis.

## Abstract

This study aimed to explore the causal effects of lipidome on Alzheimer's disease (AD) and the mediated effects of the metabolites using Mendelian randomization (MR).

Data were obtained in genome‐wide association studies, and single‐nucleotide polymorphisms were screened according to the underlying assumptions of MR. Subsequently, weighted inverse variance was used to analyze the causality of lipidome with AD as well as the mediated effects of metabolites. Finally, MR‐Egger, Cochran's Q, and sensitivity analysis were used to assess horizontal pleiotropy, heterogeneity, and robustness of the results, respectively.

The MR analysis showed that phosphatidylcholine (PC) (15:0_18:2) (mediated proportion: 18.30%, p = 0.024) and phosphatidylethanolamine (PE) (18:0_18:2) (mediated proportion: 14.60%, p = 0.028) mediated the reduction of AD risk by lowering betaine levels, which revealed lipidomic susceptibility. The MR‐Egger intercept showed no horizontal pleiotropy for all results (p ≥ 0.05). Cochran's Q showed heterogeneity in some of the results. Sensitivity analysis indicated that all results were robust.

Our findings reveal the pathways through which PC (15:0_18:2) and PE (18:0_18:2) mediated the reduction of AD risk by lowering betaine levels.

The Mendelian randomization analysis suggested that phosphatidylcholine (15:0_18:2) and phosphatidylethanolamine (18:0_18:2) reduced genetic susceptibility to Alzheimer's disease (AD) by lowering betaine levels. This finding offers new genetic insights into understanding the pathogenesis and developing novel drugs for AD.