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2017 Grants - Brinton
Perimenopause in the ApoE4 Brain: Accelerated Myelin Catabolism for Fuel
Roberta Diaz Brinton, Ph.D.
University of Arizona Health Sciences
2017 Sex and Gender in Alzheimer’s (SAGA) Grant
Does the loss of estrogen in mid-life promote Alzheimer’s disease in women who have a genetic risk factor for dementia?
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. A woman’s brain health, for example, may be affected more strongly than a man’s by the presence of APOE-e4, a gene variant linked to Alzheimer’s risk. Moreover, age-related hormonal changes in women, especially the loss of estrogen, can also impact brain function. Much of this estrogen loss takes place during perimenopause, a period that precedes menopause. Estrogen loss can hinder the brain’s ability to convert glucose (blood sugar) into energy, forcing it to find other energy sources. Such changes may place the brain under stress in ways that could increase risk for dementia, especially in women with APOE-e4.
Roberta Diaz Brinton, Ph.D., and colleagues have found that aging female brains can break down their own white matter (the brain’s “wiring system”) to provide the energy they can no longer obtain through glucose. Specifically, there is breakdown of a compound called myelin, the fatty material that insulates the wiring system needed for brain cell communication. Dr. Brinton’s team hypothesizes that the loss of myelin during perimenopause, when combined with the presence of APOE-e4, may place certain women at higher risk for Alzheimer’s disease. For their current grant, the researchers will test their hypothesis using aging female mice genetically engineered to have the human APOE-e4 gene. They will also determine whether progesterone (a female sex hormone) can be used to help prevent myelin loss and cognitive decline in the mice.
The results of this study could clarify how hormonal factors and APOE-e4 may interact to promote brain changes associated with Alzheimer’s. A better understanding of these early mechanisms could inform the development of novel methods for preventing or treating Alzheimer’s disease.