Weight matters: Higher BMI is associated with changes in the brain connectome in health and depression

Overweight and obesity are bidirectionally associated with major depressive disorder (MDD). However, the underlying mechanisms remain unknown. Here, we investigated whether the body mass index (BMI) is associated with alterations in the structural brain connectome of healthy participants and MDD patients and if these changes in connectivity are associated with clinical outcomes. We analyzed the association of BMI with structural brain connectivity in 746 MDD patients and 852 healthy controls from the Marburg-Münster Affective Disorders Cohort Study (MACS). The structural connectome was reconstructed using tractography in diffusion-weighted magnetic resonance imaging data. Associations between BMI brain connectivity were examined using network-based statistics (NBS). NBS identified a subnetwork of the brain connectome associated with BMI (F-threshold = 4.0, p _FWE < 0.05). The number of streamlines within this network were positively correlated with BMI (β = 56.122, SE = 5.50, t = 10.204, p < 0.001, R² = 0.206), suggesting that an increase in BMI is linked to enhanced connectivity within the network. This association did not differ between healthy controls and MDD patients. BMI was further associated with depression severity ( $\tau$ _BDI = 0.052, p = 0.002) and anhedonia ( $\tau$ _SHAPS-D = 0.035, p = 0.034) across all participants, independent of diagnostic status. However, after controlling for BMI, connectivity within the BMI-associated subnetwork was not related to depression severity or anhedonia, suggesting that BMI-related brain connectivity alterations do not independently explain clinical symptom severity. Our findings reveal an association between BMI and structural brain connectivity, both in healthy controls and MDD patients. These findings indicate that increased body weight has a significant association with the brain structural connectome.