2023 Sex and Gender in Alzheimer’s (SAGA) Grant (SAGA)
Interaction of ovarian hormones and APOE4 in Alzheimer's disease
How does menopause contribute to risk of Alzheimer’s, and are individuals with certain genes more likely to benefit from hormone replacement therapy?
Sarah Renee Ocanas, Ph.D.
Oklahoma Medical Research Foundation
Oklahoma City, OK - United States
Background
According to the 2023 Alzheimer’s Association Facts & Figures report, of the more than 6.5 million Americans aged 65 and older with Alzheimer’s, nearly two-thirds are women. However, the reasons underlying sex differences in Alzheimer’s remain unclear.
One idea is that the decline in estrogen during menopause puts women are at higher risk for Alzheimer’s. Studies suggest that early menopause correlates with more severe Alzheimer’s progression. Some studies indicate that hormone replacement therapy within 10 years of menopause may protect against Alzheimer’s. However, the mechanism by which a lack of estrogen could lead to changes in the brain is not well understood.
In initial studies, Dr. Ocañas found that aged female mice have more markers in their microglia (the primary immune cells in the brain) that are associated with disease in the brain. Microglia serve as one of the first defenses against nerve cell damage. They sense and help remove unwanted proteins from the brain, such as beta-amyloid, which is a hallmark brain change that can accumulate in Alzheimer’s. It is important to understand whether decreased estrogen during menopause could drive microglia to a more reactive state that contributes to the increased risk of Alzheimer’s.
Research Plan
To better understand how menopause impacts risk of Alzheimer’s, Dr. Ocañas will use genetically engineered Alzheimer’s-like mice with different genetic backgrounds that mimic Alzheimer’s risk genes. Then they will give female mice a drug that causes a gradual hormone decline to simulate menopause, then some mice will be given hormone replacement therapy, while others will not. The researchers will assess cognition in the groups of mice, as well as in male Alzheimer’s-like mice that have not been given treatments. They will also examine what genes are turned “on” or “off” in the mice’s microglia to see how they change with menopause and with or without hormone replacement therapy.
Additionally, they will genetically engineer Alzheimer’s-like mice to not have estrogen receptors in their microglia and see if that changes their development of Alzheimer’s or changes the outcome of hormone replacement therapy.
Impact
The results of this study will help provide information about how menopause and hormone replacement therapy contribute to risk of Alzheimer’s and predict the populations likely to benefit from hormone replacement therapy.