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2024 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

Understanding the Negative Impact of APOE4 on Neural Responses to Estrogens

How could adjusting estrogen levels in older women benefit brain health and impact Alzheimer’s risk?

Karyn Frick, Ph.D.
University of Wisconsin-Milwaukee
Milwaukee, WI - United States


According to the 2023 Alzheimer’s Association Facts & Figures report, of the approximately 6.9 million Americans aged 65 and older with Alzheimer’s disease, nearly two-thirds are women. Age is the most prominent risk factor for Alzheimer’s, but there are certain genetic risk factors that can also increase risk. One genetic risk factor in some populations is apolipoprotein E (APOE), a gene with several variations (APOE-e2, APOE-e3, and APOE-e4). Possessing the APOE-e4 variation is thought to increase the risk of Alzheimer’s in some individuals, and research suggests women with two copies of APOE-e4 are at an even higher risk of developing the disease than women carrying other APOE variations.

Scientists are also exploring other biological mechanisms that may explain why women are at higher risk for Alzheimer’s. One such mechanism involves sex hormones, specifically during menopause. Levels of certain hormones, including estrogen, drop in the body during menopause. Hormone therapy is used to manage menopause symptoms, such as hot flashes and fatigue, and some studies suggest that hormone therapy may also be protective of brain health in women who have one or two copies of APOE-e4. Other studies, however, indicate that among women on estrogen hormone therapy, those with APOE-e4 experience faster rates of cognitive (brain function) decline than those without APOE-e4. Understanding how hormone therapy may impact women carrying APOE-e4 will help clarify the biology underlying female Alzheimer’s risk. 

Research Plan

Dr. Karyn M. Frick and colleagues received additional funding to build upon their 2022 APOE Biology in Alzheimer’s (ABA) grant to expand their work on APOE, estrogen, and Alzheimer’s. The researchers are testing a compound called EGX358 in female, genetically-engineered Alzheimer’s-like mice that carry different variations of APOE. EGX358 helps activate a receptor (a protein on the cell's surface that allows for signaling through the cell) called the estrogen receptor (ER)-beta. ER-beta is one of the main proteins that recognize estrogen in the body. 

For their supplemental award, Dr. Frick and team will look for biological mechanisms that may underlie how ER-beta activation impacts brain health. Specifically, they will examine how EGX358 treatment affects specific dementia-related protein levels and brain cell activity in their female Alzheimer’s-like mice.    


Dr. Frick’s study will offer a comprehensive approach to understanding the links between estrogen levels, APOE-e4, and Alzheimer’s-related brain changes in women. If successful, such work could lead to safer, more effective estrogen treatments to protect women’s brain health as they age and undergo menopause.

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