Association between Body Mass Index and Brain Health in Adults: A 16-Year Population-Based Cohort and Mendelian Randomization Study

Background: The cumulative effect of body mass index (BMI) on brain health remains ill-defined. The effects of overweight on brain health across different age groups need clarification. We analyzed the effect of cumulative BMI on neuroimaging features of brain health in adults of different ages. Methods: This study was based on a multicenter, community-based cohort study. We modeled the trajectories of BMI over 16 years to evaluate cumulative exposure. Multimodality neuroimaging data were collected once for volumetric measurements of the brain macrostructure, white matter hyperintensity (WMH), and brain microstructure. We used a generalized linear model to evaluate the association between cumulative BMI and neuroimaging features. Two-sample Mendelian randomization analysis was performed using summary level of BMI genetic data from 681,275 individuals and neuroimaging genetic data from 33,224 individuals to analyze the causal relationships. Results: Clinical and neuroimaging data were obtained from 1,074 adults (25 to 83 years). For adults aged under 45 years, brain volume differences in participants with a cumulative BMI of >26.2 kg/m 2 corresponded to 12.0 years [95% confidence interval (CI), 3.0 to 20.0] of brain aging. Differences in WMH were statistically substantial for participants aged over 60 years, with a 6.0-ml (95% CI, 1.5 to 10.5) larger volume. Genetic analysis indicated causal relationships between high BMI and smaller gray matter and higher fractional anisotropy in projection fibers. Conclusion: High cumulative BMI is associated with smaller brain volume, larger volume of white matter lesions, and abnormal microstructural integrity. Adults younger than 45 years are suggested to maintain their BMI below 26.2 kg/m 2 for better brain health. Trial Registration: This study was registered on clinicaltrials.gov (Clinical Indicators and Brain Image Data: A Cohort Study Based on Kailuan Cohort; No. NCT05453877; https://clinicaltrials.gov/ct2/show/NCT05453877 ).