Grant: Canada Postdoctoral Research Award (CPRA) program

Alzheimer Disease (AD) prevalence rates are climbing, with costs estimated at $40B in Canada alone in 2020. Women are more likely to be diagnosed with AD and show greater brain pathology and memory loss with the disease than men. In addition, women are more likely to develop AD, especially when they have certain genes such as APOE4 (a gene variant that increases AD risk). Menopause is a midlife transition unique to females, which may also play an important role in brain aging and AD risk. Menopause is associated with dramatic changes in hormone levels and with cognitive decline, and its effects can differ depending on whether it occurs naturally or surgically. Certain Menopause Hormone Therapies (MHT) positively affect cognition depending on menopause type, APOE genotype and route of administration. This project aims to investigate how different menopause type and MHTs affect AD-related brain changes and cognitive functions in female mice with APOE4 and APOE3 genetic variants. In these experiments, we will evaluate how menopause and MHT type modulate gene expression and key signaling pathways in the hippocampus, a brain region important for memory and strongly affected in AD. We will also study cognition, as well as hippocampal structure and function. Finally, we will explore the role of microglia - the brain's resident immune cells, which protect the brain from damage and have been implicated in AD - in mediating the effects of MHTs. Our research will open avenues for new therapeutics in AD and inform precision treatment based on menopause and MHT type in middle age, a key period for early intervention.