Life Course Adiposity and Alzheimer's Disease: A Mendelian Randomization Study

Several studies showed that life course adiposity was associated with Alzheimer's disease (AD). However, the underlying causality remains unclear.

We aimed to examine the causal relationship between life course adiposity and AD using Mendelian randomization (MR) analysis.

Instrumental variants were obtained from large genome-wide association studies (GWAS) for life course adiposity, including birth weight (BW), childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), and body fat percentage (BFP). A meta-analysis of GWAS for AD including 71,880 cases and 383,378 controls was used in this study. MR analyses were performed using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. We calculated odds ratios (ORs) per genetically predicted standard deviation (1-SD) unit increase in each trait for AD.

Genetically predicted 1-SD increase in adult BMI was significantly associated with higher risk of AD (IVW: OR = 1.03, 95% confidence interval [CI] = 1.01-1.05, p = 2.7×10-3) after Bonferroni correction. The weighted median method indicated a significant association between BW and AD (OR = 0.94, 95% CI = 0.90-0.98, p = 1.8×10-3). We also found suggestive associations of AD with WC (IVW: OR = 1.03, 95% CI = 1.00-1.07, p = 0.048) and WHR (weighted median: OR = 1.04, 95% CI = 1.00-1.07, p = 0.029). No association was detected of AD with childhood BMI and BFP.

Our study demonstrated that lower BW and higher adult BMI had causal effects on increased AD risk.