Hamilton, Victoria2024-07-302024-07-302024-07-30http://hdl.handle.net/10393/46427https://doi.org/10.20381/ruor-30459Alzheimer's disease (AD) is a neurodegenerative brain disease characterized by memory impairment and progressive cognitive decline that leads to dementia. While a small subset (<5%) of AD cases, known as familial AD (fAD), are due to three genetic determinants (APP, PSEN-1, PSEN-2), we still do not understand the cause behind 95% of AD cases, known as sporadic AD (sAD) which are idiopathic and late-onset (> 65 years of age). Women represent two-thirds of clinically diagnosed AD cases and disproportionally experience accelerated trajectories to cognitive decline compared to men. The N5 TgCRND8 mouse model is an aggressive mouse model of Aß deposition that exhibits sexual dimorphisms in behavioural indices of cognitive decline (Chisti et al., 2001; Granger et al., 2016). In this thesis I investigated how age and sex interact with Aß load to elicit behavioural indices of ADL (i.e., nesting, sleeping, eating, drinking), BPSD (i.e., sleep-wake cycle, motoric hyperarousal, anxiety) and cognition (learning, memory, and strategy/cognitive reserve) in the N5 TgCRND8 model. First, I show that Tg females and Tg males exhibit comparable longitudinal Aß (Aß40 and Aß42) levels in the temporal cortex and hippocampus as they age from 2-12 months of age. I next characterized behavioural indices of ADL and BPSD in the N5 TgCRND8 mouse model using a battery of behavioural tests. Data presented here show that young N5 TgCRND8 mice exhibit ADL impairment and a hyperaroused phenotype that may contribute to behavioural indices of wake-dysfunction. Lastly, I investigated behavioural indices of cognition (visuospatial working memory, visuospatial learning and memory, cognitive reserve) in the N5 TgCRND8 mouse model. I show that sex-specific impairments in visuospatial working memory, visuospatial learning and memory and cognitive reserve in N5 TgCRND8 mice occurred later in life both after the onset of ADL and BPSD impairments and under identical longitudinal Aß (Aß40 and Aß42) challenge between females and males. Taken together, this thesis provides converging evidence to indicate that age and sex interact with initial (biological) AD neuropathology to elicit early ADL and BPSD behavioural impairment in N5 TgCRND8 mice that later manifests as sex-specific cognitive decline.enAlzheimer's diseaseDementiaN5 TgCRND8Sex differencesThesis