Grant: Doctoral Research Award: Canada Graduate Scholarships

Alzheimer's disease (AD) is the most common form of dementia, causing progressive memory loss and damage to the brain. Two-thirds of people with AD are female, and many carry a genetic risk factor called the APOE4 gene variant. Although hormone therapies, like estradiol (the most potent estrogen), may reduce AD risk, we don't fully understand how other modifiable factors, such as diet, play a role in this protection. Obesity and type 2 diabetes, for instance, can increase AD risk, while a hormone called GLP-1 helps manage appetite and blood sugar. Furthermore, when combined with estradiol they can form a conjugated drug called conjugated GLP-1 estradiol (GE2). GE2 therapy has shown promise in reducing body weight without the typical side effects of estrogen. The effects GE2 can have on memory and brain health in both males and females remain unclear. In this study, we aim to explore whether GE2 improves memory and reduces brain inflammation in male and female mice with genetic risk factors for AD, particularly under conditions that will cause obesity. Half of the mice will be fed a high-fat, high-sugar diet to induce obesity, and then given either GE2 or a placebo while still on the diet. We will then test their memory and examine their brains and see how GE2 affects new brain cell growth and inflammation, which are both important for brain health and AD risk. We believe that GE2 will protect against AD-related brain changes, especially in females, by reducing brain inflammation. This research will help us better understand how GE2 works as a potential treatment for AD, how sex differences play a role, and whether obesity impacts its effectiveness. These insights could lead to new, more targeted therapies for all sexes.