A mendelian randomization analysis of obesity on the development of Alzheimer’s disease

Purpose: To assess the causal associations between obesity and Alzheimer’s disease (AD) using Mendelian randomization analysis based on summary statistics from genome-wide association studies (GWAS). The most recent GWAS as of November 2021 for AD and obesity were used, including newly identified risk single nucleotide polymorphisms (SNPs) that were associated with AD and obesity. Specifically, the AD GWAS identified 42 new risk loci, which have not been utilized in other studies. Thus, this study provides novel evidence for the causal associations of AD and obesity.

Methods: Genetic associations for the exposure (i.e., obesity; BMI ≥ 30kg/m2) were evaluated from a GWAS conducted on European individuals over age 18 in the FinnGen project (n = 218,792). Genetic associations for AD were evaluated from the whole exome sequencing data among European individuals aged 37-73 years in the UK Biobank study (n = 111,326 AD cases and 677,633 controls). Based on the above summary statistics, a Two Sample Mendelian randomization (MR) analysis using the Inverse-Variance Weighted (IVW) method was conducted to evaluate the causal association between obesity and AD. Sensitivity analyses including median-based, mode-based, and MR-Egger MR methods were conducted to confirm findings from the main MR analysis.

Results: Obesity was found to be associated with a decreased odds in the development of AD (Odds ratio = 0.91, 95% CI = [0.86, 0.95], p = 0.0001) according to the IVW method, suggesting a protective effect of obesity. The results of all sensitivity analyses were consistent with the main findings and determined the absence of horizontal pleiotropy and heterogeneity. Specifically, significant causal relationship between AD and obesity was identified in the IVW method and Weighted Median MR methods.

Conclusion: The protective effect of obesity on the development of AD is supported by the MR analysis in this study. Further research should be conducted on the underlying pathological mechanism to inform potential health interventions such as weight modification in mid versus late life.