Abstract
BACKGROUND: Adipose tissue and the central nervous system regulate each other, but the interactions between body fat composition and brain health remain unclear. METHODS: To investigate this, we conducted Mendelian randomization (MR) analyses to explore the causality between body fat composition, brain volume, intelligence, cognitive performance (CP), and 19 neuropsychiatric diseases using six body fat measures. We performed cross-trait meta-analysis and colocalization analysis for body mass index (BMI) with Alzheimer’s disease (AD) and Parkinson’s disease (PD). RESULTS: Our findings show that higher body fat composition is associated with smaller grey matter volume, reduced intelligence and CP, increased risks of 10 neuropsychiatric diseases, and decreased risks of others. Additionally, certain brain diseases exert causal effects on body fat. We identified a novel AMDP1-containing genomic locus shared between BMI and PD. Adenosine signaling was highlighted as a cross-talking pathway with opposing effects on PD and BMI-related phenotypes. CONCLUSIONS: These results highlight the bidirectional fat-brain axis and suggest the need for disease-specific weight management strategies. TRIAL REGISTRATION: Not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07453-8.