Non-linear, sex-modulated trajectories of Aβ-driven cognitive decline across aging in the McGill-R-Thy1-APP Rat Model of Alzheimer’s-Like Brain Amyloidosis

Alzheimer's disease (AD) progression is influenced by aging and sexual dimorphism, but their interaction with early amyloid accumulation remains unclear. This study longitudinally evaluated cognitive performance—across Open Field (OF), Inhibitory Avoidance (IA), Novel Object Recognition (NOR), and Novel Object Location (NOL) tasks—and amyloid burden in male and female McGill-R-Thy1-hAPP (Tg+/-) and wild-type rats at 4 and 12 months. Intraneuronal human Aβ (hAβ) distribution and hippocampal soluble Aβ40/Aβ42 levels were measured. To map relative cognitive metrics against hippocampal Aβ42 concentrations, NOR was selected over alternative tasks (OF, NOL, IA) because it permits concurrent isolation of short- and long-term memory kinetics within the same cohort and sensory modality. hAβ immunoreactivity was exclusive to Tg+/- rats (cortex and hippocampus). Soluble Aβ40/Aβ42 levels showed sex-dependent dynamics: males had higher concentrations at 4 months, whereas females exhibited a larger increase at 12 months. However, despite higher late-stage amyloid burden, females preserved lower functional sensitivity to Aβ42 accumulation. In contrast, males showed more pronounced cognitive decline with smaller Aβ42 increases, displaying steeper sensitivity slopes. These results demonstrate that Aβ-driven cognitive decline is non-linear and sex-modulated. Integrating sexual dimorphism into preclinical AD detection is essential for precision medicine strategies.