Association between obesity, brain atrophy and accelerated brain aging and their genetic mechanisms

Objective: To investigate the causal relationship and the underlying biological mechanisms between body mass index (BMI) and grey matter volume (GMV). Methods: We applied Mendelian randomization analyses utilizing 33,6514 individuals from the UK Biobank cohort to establish the causal relationship between BMI and GMV. We also quantified obesity-related accelerated brain aging using an XGBoost prediction paradigm. Then, mediation analyses were performed to test the association between BMI, brain atrophy, brain aging and cognitive function. Finally, the gene expression data from the Allen Human Brain Atlas were used to identify genes contributing to the BMI-GMV association. Results: A causal effect of increased BMI on decreased GMV was established using multiple Mendelian randomization methods. The brain age prediction paradigm achieved appreciable performance in both training (R = 0.725, mean-absolute-error (MAE) = 4.130) and test data (R= 0.71, MAE = 4.239). On average, overweight and obese individuals exhibited significantly accelerated brain aging by +0.59 years and +1.7 years, respectively. Further, the accelerated brain age and total GMV mediated 18% of the association of higher BMI with poorer cognitive function. BMI-associated lower GMVs were related to the over-expression of gene TRIM27 and other genes involved in the autophagy biological process. Conclusion: Obesity led to GMV decline and accelerated brain aging. Genes including TRIM27 and biological process pathways involved in autophagy may contribute to the BMI-GMV association.