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2017 Grants - Frick
Estradiol-APOE Interactions in a Mouse Model of Alzheimer’s Disease
Karyn M. Frick, Ph.D.
University of Wisconsin-Milwaukee
2017 Sex and Gender in Alzheimer’s (SAGA) Grant
Do variations in the APOE gene impact the effects of estrogen on brain function and the risk for developing Alzheimer’s disease?
Women are disproportionately affected by Alzheimer’s disease and emerging evidence suggests there may be unique biological and lifestyle factors that underlie these differences. Scientists are actively working to address gaps in our understanding of how biological sex and related genetic, lifestyle and societal factors may impact vulnerability to Alzheimer’s disease. Research has shown that women with APOE-e4 (a gene variant known to promote Alzheimer’s) may be more vulnerable to disease risk then men this variant, but the underlying mechanisms are not yet understood. One possibility is that APOE-e4 may interact with other factors linked to sex-differences in Alzheimer’s disease including changes in estrogen levels during aging. Estrogen replacement therapy during menopause is associated with greater rates of cognitive decline in women with APOE-e4 compared to women without APOE-e4. While this suggests that APOE-e4 and estrogen may interact to promote brain cell dysfunction and damage, the exact nature of this interaction remains unknown.
In initial studies using Alzheimer’s-like mice, Karyn M. Frick, Ph.D., and colleagues found that estrogen differentially affects the brain depending on the sex of the mice and whether they have the APOE-e4 genetic variation. For example, estrogen increased the levels of beta-amyloid in the brains of female mice with APOE-e4, while it decreased beta-amyloid in female mice without this variant. Accumulation of beta-amyloid (“plaques”) in the brain is a hallmark of Alzheimer’s disease. For their current research grant, Dr. Frick and colleagues hope to clarify how sex, estrogen and APOE-e4 impact brain changes associated with Alzheimer’s disease. Their work will involve male and female mice that are engineered to have either APOE-e4 or the more common, and less harmful gene variant, called APOE-e3. They will also examine how the different mice are affected by estrogen treatment. The researchers will study how these factors interact to promote changes in nerve cell communication and cognitive function in the mice.
The results of this work could shed new light on how hormones and genetics may interact to promote Alzheimer’s risk in both women and men. Importantly, a better understanding of these biological mechanisms can inform ways to reduce risk or develop targeted treatments to slow or prevent Alzheimer’s disease.