This cohort study investigates the long-term associations between weight loss induced by bariatric surgery (BS) and cognition, brain structure, and perfusion. The study included 133 participants with severe obesity who underwent Roux-en-Y gastric bypass and were followed for up to 24 months post-surgery. Key findings include: - **Cognition**: Global cognition improved in 42.9% of participants at 24 months post-surgery, with significant improvements in attention and verbal fluency. - **Comorbidities**: Medication use for comorbidities decreased, and depressive symptoms and physical activity increased. - **Brain Structure and Perfusion**: Most brain regions showed lower volumes and cerebral blood flow (CBF) but remained stable in some regions, such as the hippocampus and white matter. The temporal cortex exhibited higher cortical thickness and lower spatial coefficient of variation (sCOV), indicating improved vascular efficiency. - **Adipokines and Inflammatory Factors**: Circulating markers of inflammation and adipokines showed significant changes over time, with lower levels of inflammatory markers and higher levels of adiponectin and neurofilament light chain (NFL) at 24 months post-surgery. The study suggests that BS is associated with long-term health benefits, including improved cognition, comorbidities, and inflammation, as well as changes in brain structure and function. These findings highlight the potential of BS as a treatment option for obesity and related neurological conditions.This cohort study investigates the long-term associations between weight loss induced by bariatric surgery (BS) and cognition, brain structure, and perfusion. The study included 133 participants with severe obesity who underwent Roux-en-Y gastric bypass and were followed for up to 24 months post-surgery. Key findings include: - **Cognition**: Global cognition improved in 42.9% of participants at 24 months post-surgery, with significant improvements in attention and verbal fluency. - **Comorbidities**: Medication use for comorbidities decreased, and depressive symptoms and physical activity increased. - **Brain Structure and Perfusion**: Most brain regions showed lower volumes and cerebral blood flow (CBF) but remained stable in some regions, such as the hippocampus and white matter. The temporal cortex exhibited higher cortical thickness and lower spatial coefficient of variation (sCOV), indicating improved vascular efficiency. - **Adipokines and Inflammatory Factors**: Circulating markers of inflammation and adipokines showed significant changes over time, with lower levels of inflammatory markers and higher levels of adiponectin and neurofilament light chain (NFL) at 24 months post-surgery. The study suggests that BS is associated with long-term health benefits, including improved cognition, comorbidities, and inflammation, as well as changes in brain structure and function. These findings highlight the potential of BS as a treatment option for obesity and related neurological conditions.