Association Between Leptin, Cognition, and Structural Brain Measures Among "Early" Middle-Aged Adults: Results from the Framingham Heart Study Third Generation Cohort.

Background: There is growing interest in the pathophysiological processes of preclinical Alzheimer's disease (AD), including the potential role of leptin. Human studies have shown that both low and high levels of leptin can be associated with worse neurocognitive outcomes, suggesting this relationship may be moderated by another risk factor. Objective: We examined the association between plasma leptin levels and both neuropsychological test performance and structural neuroimaging and assessed whether body mass index (BMI) is an effect modifier of these associations. Methods: Our study sample consisted of 2,223 adults from the Framingham Heart Study Third Generation Cohort (average age = 40 years, 53% women). Results: Among the entire sample, there was no association between leptin and any of the neuropsychological domain measures or any of the MRI brain volume measures, after adjustment for BMI, APOE4, and other clinical factors. However, we did observe that BMI category was an effect modifier for the association between leptin and verbal memory (p for interaction = 0.03), where higher levels of leptin were associated with better performance among normal weight participants (BMI 18.5-24.9) kg/m(2) (beta = 0.12, p = 0.02). No association was observed between leptin level and verbal memory test performance among participants who were overweight or obese. Conclusion: These findings suggest that the association between leptin and cognitive function is moderated by BMI category. Prospective examination of individuals transitioning from middle age to older adulthood will help to clarify the contribution of leptin to AD and other neurodegenerative conditions.