Biomarkers

Abstract

Background: Obesity in midlife, defined as body mass index (BMI) of 30 kg/m² or higher in those between 40-60 years, is related to higher Alzheimer's disease (AD) later in life. Non-alcoholic fatty liver disease, as a complication of obesity is associated with impaired cognitive function. We investigated the relationship between hepatic fat quantification by use of MRI-derived Positron Density Fat Fraction (PDFF) and brain cortical thickness in cognitively normal midlife individuals.

Method: Overall, 63 cognitively normal middle-aged participants (Age: 50.46±6.19 years, female: 22 (71%), obesity: 32 (50.28 %), BMI: 36.46±4.9 kg/m²) underwent brain and abdominal 3T MRI. PDFF values were calculated using a trained U-Net convolutional neural network (CNN) model to infer the hepatic PDFF maps from conventional T1-weighted images. The CNN included the Adam optimizer for training with a learning rate of 1e-4. Visceral and subcutaneous adipose tissue (VAT, SAT) were automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer 7.1.1 was used for automatic segmentation of cortical and subcortical brain regions using a probabilistic atlas, followed by visual inspection and if needed, manual editing. A multivariable linear regression analysis was carried out to test the association of PDFF, VAT, SAT, and BMI with brain cortical thickness, with age and sex as covariates.

Result: We observed a statistically significant association between PDFF and VAT (p=3e-7), BMI (p=2e-4), and insulin resistance (1e-4). Among late-onset AD (LOAD) cortical regions, there was a significant inverse correlation (Adjusted R²=0.19, p<0.001) between left temporal pole thickness and PDFF. Similarly, higher VAT was associated with thinning in left temporal pole (Adjusted R²=0.22, p<0.001) and middle temporal lobe (Adjusted R²=0.12, p=0.014).

Conclusion: Overall, our data suggest a potential role of hepatic fat fraction in promoting neurodegeneration in cognitively normal midlife individuals. These findings lend insight into a pathway that can be utilized for future AD risk reduction.