Abstract
The impact of obesity on brain health, spanning cerebrovascular disease, cognition, and neuroanatomy, remains incompletely understood. We conducted 2-sample Mendelian randomization to assess the causal effects of obesity traits on brain health outcomes. Potential biological pathways were explored using transcriptome-wide association study analyses. We further examined associations in the National Health and Nutrition Examination Survey using weighted, multivariable-adjusted logistic regression. Obesity measures included body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR). Outcomes comprised stroke, fluid intelligence, and brain image-derived phenotypes. Higher BMI (odds ratio [OR] = 1.18; 95% confidence interval [CI], 1.13-1.24; P = 8.99 × 10-12), WC (OR = 1.20; 95% CI, 1.09-1.31; P = 3.85 × 10-3), and WHR (OR = 1.23; 95% CI, 1.16-1.31; P = 9.19 × 10-11) were associated with increased stroke risk. BMI (β = -0.21; P = 8.62 × 10-6) and WHR (β = -0.33; P = 1.19 × 10-7) were linked to lower fluid intelligence scores. BMI showed causal effects on 7 brain image-derived phenotypes. Transcriptome-wide association study implicated pathways related to substrate metabolism, immune activation, and epigenetic regulation in mediating obesity's effects on brain health. In National Health and Nutrition Examination Survey, after adjustment for covariates, BMI (OR = 1.04; 95% CI, 1.02-1.06; P = 1.27 × 10-3), WC (OR = 1.01; 95% CI, 1.00-1.02; P = 9.58 × 10-3), and WHR (OR = 1.40; 95% CI, 1.08-1.81; P = 1.25 × 10-2) were positively associated with stroke risk. Obesity, particularly BMI, shows causal relationships with stroke risk, alterations in brain structure, and reduced cognitive performance. Mechanisms may involve metabolic, immune, and epigenetic pathways. These findings underscore the importance of obesity prevention and management to preserve brain health.