Mid-life obesity is an established risk factor for Alzheimer's disease (AD) dementia, whereas late-life obesity has been proposed as a protective state. Weight loss, which predates cognitive decline, might explain this obesity paradox on AD risk. We aimed to assess the impact of late life obesity on brain structure taking into account weight loss as a potential confounder. We included 162 elderly controls of the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available 3T MRI scan. Significant weight loss was defined as relative weight loss ≥5% between the baseline and last follow-up visit. To be able to capture weight loss, only subjects with a minimum clinical and anthropometrical follow-up of 12 months were included. Individuals were categorized into three groups according to body mass index (BMI) at baseline: normal-weight (BMI<25 Kg/m2), overweight (BMI 25-30 Kg/m2) and obese (BMI>30 Kg/m2). We performed both an interaction analysis between obesity and weight loss, and stratified group analyses in the weight-stable and weigh-loss groups. We found a significant interaction between BMI and weight loss affecting brain structure in widespread cortical areas. The stratified analyses showed atrophy in occipital, inferior temporal, precuneus and frontal regions in the weight stable group, but increased cortical thickness in the weight-loss group. In conclusion, our data support that weight loss negatively confounds the association between late-life obesity and brain atrophy. The obesity paradox on AD risk might be explained by reverse causation.
Keywords: body mass index; magnetic resonance imaging; obesity; preclinical Alzheimer's disease; weight loss.