Sexually dimorphic association of circulating leptin levels with early amyloid‐beta pathology assessed by amyloid PET

Abstract

AbstractBackgroundWeight loss can precede the cognitive decline in Alzheimer’s Disease (AD), suggesting that mechanisms regulating body weight such as the adipocyte hormone leptin are an early target of AD pathology (Cell Metabolism 22:761,2015). In mouse models, we previously found that amyloid‐beta pathology can cause hypothalamic dysfunction that was associated with low body adiposity and low plasma leptin levels prior to significant memory impairment (J Neuroscience 34:9096,2014). In this study, we sought to determine if circulating leptin levels are associated with brain amyloid‐beta pathology, assessed by amyloid PET, in individuals with normal cognition or mild cognitive impairment (MCI).MethodThis cross‐sectional study involved community dwelling volunteers originally recruited for the Imaging and Genetic Biomarkers for AD (ImaGene) study. All subjects were age ≥ 50 years, normal cognition or MCI as defined by Clinical Dementia Rating (CDR) score of 0 or 0.5 respectively, and underwent PET scan using the amyloid‐beta tracer 18F‐flutemetamol. Subjects were classified as positive for amyloid‐beta pathology if standard uptake value ratios (SUVr) ≥ 1.27. Serum leptin levels were measured by enzyme linked immunosorbent assay and log transformed. Multiple linear regression analysis was used to examine correlations between serum leptin levels and amyloid PET SUVr.ResultIn men, body mass index (BMI) and serum leptin levels were significantly lower in amyloid PET positive subjects (n = 12) compared to control subjects (n = 8). Furthermore, BMI and serum leptin levels were significantly associated with amyloid PET SUVr (BMI: age‐adjusted β coefficient = ‐0.53, p = 0.018; leptin: age‐adjusted β coefficient = ‐0.69, p = 0.002). However, in women, BMI and serum leptin levels were not significantly different between control and amyloid PET positive subjects and were not associated with amyloid PET SUVr (12 control and 5 amyloid PET positive subjects, all p > 0.05).ConclusionThese studies raise the possibility that, in men, amyloid‐beta pathology causes alterations in leptin signaling and metabolic dysfunction early in AD. Studies in larger cohorts will be needed to confirm these observations and to help determine their clinical utility as well as the underlying mechanisms of the sex differences.