Alzheimer’s disease (AD) disproportionately affects women, who account for nearly two-thirds of all cases. Making matters worse, Alzheimer’s risk is further amplified in women carrying the APOE4 gene. Most cases of AD in women are diagnosed after menopause, when a natural decline in ovarian hormones coincides with early changes in the hippocampus, a brain region critical for forming new memories and one of the first areas affected in AD. Understanding how hormonal changes and APOE4 interact to influence genetic risk is important, as it could reveal why some women are more susceptible to cognitive decline. While menopausal hormone therapy (MHT) has shown promise as being protective for the brain, clinical results have been inconsistent. This inconsistency likely occurs because studies have not accounted for important differences in how menopause begins—whether naturally, through surgical removal of the ovaries, or through chemical induction—or in the delivery method for estrogen replacement therapies (oral pill, skin patch, or injection beneath the skin). All of these factors influence how estrogen affects the brain.
In their previous CureAlz-funded project, Drs. Galea and Ciernia have shown that the hippocampus is highly sensitive to estrogen loss. In rodent studies, a subcutaneous (beneath the skin) injection of estradiol, the most potent form of estrogen, enhances hippocampal plasticity and memory. However, when estradiol is taken orally as a pill, it is broken down into estrone, which has weaker or even negative effects on the hippocampus. In humans, estradiol skin patches also improve hippocampal function, highlighting the importance of maintaining circulating estradiol levels to support brain health. Preliminary data further link estrogen’s effects to APOE4 and immune activity. In female mice carrying the human APOE4 gene, the researchers observed increased inflammation and overactive microglia, the brain’s immune cells, which led to impaired formation and survival of new neurons. These findings suggest that estrogen may protect the female brain by regulating immune activity and supporting neurogenesis. Both of these processes are disrupted in females at higher risk for AD. Based on these observations, the team hypothesizes that subcutaneous estradiol will improve hippocampus-dependent cognition and neuroplasticity and reduce AD-related pathology in middle-aged female mice, with outcomes influenced by both menopause type and APOE genotype. They further hypothesize that these benefits are mediated, at least in part, through microglial activity and the complement system, an immune pathway involved in pruning synapses and newborn neurons.
To test this, they will pursue two complementary aims. In Aim 1, they will investigate how different estradiol delivery methods affect gene activity in the hippocampus. They will also explore whether APOE4 or the method of menopause onset (naturally, surgically, or chemically induced) changes the effects of estradiol delivery method on the hippocampus. They predict that subcutaneous estradiol will most effectively activate protective gene networks, particularly in non-APOE4 mice. In Aim 2, they will investigate whether the complement system (an immune pathway) mediates estradiol’s effects on the hippocampus and cognition. They will combine behavioral memory tests with measures of neurogenesis and microglial activation to determine how blocking the complement system affects the positive effects of estradiol. Manipulating this immune pathway should help explain how estrogen supports cognition and hippocampal health, as well as whether the benefits differ depending on menopause type and APOE genotype.
By determining how menopause type, estradiol delivery method, and APOE genotype interact to influence brain aging, this work could explain why hormone therapy benefits some women but not others. These insights have the potential to guide personalized, safer hormone-based strategies for maintaining memory and reducing Alzheimer’s risk in women, addressing a critical unmet need for half the population.
