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

Background: Several studies showed that life course adiposity was associated with Alzheimer's disease (AD). However, the underlying causality remains unclear. Objective: We aimed to examine the causal relationship between life course adiposity and AD using Mendelian randomization (MR) analysis. Methods: 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. Results: 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 x 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 x 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. Conclusion: Our study demonstrated that lower BW and higher adult BMI had causal effects on increased AD risk.