Does menopause enhance Alzheimer’s Disease risk by exacerbating vascular dysfunction? (360G-Wellcome-313677_Z_24_Z)

The clinical burden of dementia falls primarily on females, whose lifetime risk for developing Alzheimer's disease (AD) is double males. Many risk factors for AD (e.g. APOE4) are shared with cardiovascular disease, and vascular dysfunction is observed early in neurodegeneration. Oestrogen promotes vasodilation and is depleted during menopause, which I predict contributes to female's unique susceptibility to AD. Hormone replacement therapy (HRT), the recommended treatment during menopause, aims to restore oestrogen, although clinical studies examining the impact of HRT on cognition and AD risk have been inconclusive. Limitations of previous studies include that variable genetic and lifestyle factors, including APOE status and the timing of HRT initiation, have not been accounted for. Using a preclinical mouse model with induced menopause, this project seeks to explore the impact of menopause, APOE status and age on vascular and cognitive health through in vivo imaging, behavioural testing, immunohistochemistry and RNAsequencing. Subsequently, relevant treatment options for improving vascular health will be explored by assessing the impact of the timing of HRT initiation, and alternative novel therapeutic options (identified through previous RNAsequencing) which target vasodilatory pathways impacted by menopause. Finally, the impact of menopause on amyloid plaque progression will be explored in an APP/PS1 model.