Sexual dimorphism in the peripheral metabolic homeostasis and behavior in the TgF344‐AD rat model of Alzheimer's disease

Alzheimer's disease (AD), a prevalent form of dementia, is characterized by the decline of cognitive abilities with age. Available treatment options for AD are limited, making it a significant public health concern. Recent research suggests that metabolic dysfunction plays a role in the development of AD. In addition, insulin therapy has been shown to improve memory in patients with cognitive decline. In this study, we report the first examination of body composition, peripheral insulin sensitivity, and glucose tolerance in relation to behavioral assessments of learning, memory, and anxiety in the TgF344‐AD rat model of AD. Results from glucose and insulin tolerance tests show that female TgF344‐AD rats exhibit impaired glucose clearance and reduced insulin sensitivity at both 9 and 12 months of age, while males display no differences at 9 months and even improved glucose clearance at 12 months. Results from the Morris Water Maze assessment of learning and memory reveal that male TgF344‐AD rats display impairments at both 9 and 12 months of age, while female TgF344‐AD rats only show impairments at 12 months. Furthermore, results from open field and elevated plus maze tests suggest that female TgF344‐AD rats display increased anxiety at 9 months of age; however, no differences were detected in males or at 12 months of age. Overall, our findings suggest that impairments in metabolism, commonly associated with type 2 diabetes, occur before or simultaneously with cognitive decline and anxiety in a sexually dimorphic manner in the TgF344‐AD rat model. Impaired glucose clearance and reduced insulin sensitivity were observed in female TgF344‐AD rats, while males showed no differences. Male rats had learning and memory impairments at both 9 and 12 months of age, while females showed impairments only at 12 months. The findings suggest that metabolic issues occur simultaneously with cognitive decline and anxiety in a sexually dimorphic manner in the TgF344‐AD rat model.