Women are at a higher risk than men of developing Alzheimerβs disease. So are people who carry a particular variant of a gene that everyone has, called APOE.
With a $300,000 research grant from the Alzheimerβs Association, a team of scientists, led by psychology and neuroscience distinguished professor Karyn Frick will dive into why women with two variants of the APOE gene are more protected from Alzheimerβs when they take estrogen therapy, while those with a third variant arenβt.
Almost two in three Americans with Alzheimerβs are women, according to the Alzheimerβs Association 2022 Alzheimerβs Disease Facts and Figures. The hormone estrogen protects the brain cells that create and store memories, but estrogen levels decline during menopause, leaving womenβs brains more vulnerable to the disease.
Estrogen therapy reduces the odds for some women. Previous research has shown that one of the APOE geneβs three variants, dubbed E4, shows resistance to estrogenβs brain benefits. The other variants, E2 and E3, are not resistant to estrogen therapy.
The researchersβ aim is to find the most effective estrogen compound for each APOE variant to move into human clinical trials.
βWe are excited to support this very important work being done by Dr. Frick and her colleagues,β said David Grams, executive director of the Alzheimerβs Association Wisconsin Chapter. βWe are committed to investing in promising and innovative research and weβre proud that Wisconsin is home to scientists who are dedicated to helping us find a cure for this devastating disease.β
βAll people carry two APOE variants in different combinations,β Frick said, βSo risk would be different depending on whether a woman carries the E3/3, E3/4 or E4/4 variants.β
Using an Alzheimerβs mouse model developed by another team member, Mary Jo LaDu of the University of Illinois at Chicago, the researchers will compare oral treatment of a potent estrogen called estradiol along with two novel estrogen compounds on mice that have the APOE variants E3/4 and E4/4.
These treatments target another part needed to solve the Alzheimerβs puzzle in women β estrogen receptors. In order to influence cell function estrogens must enter the cells and bind to these receptors.
APOE is a gene thatβs responsible for transporting cholesterol and other types of fats β or lipids β to cells where they can be used or disposed of. Exactly how itβs involved in womenβs risk of Alzheimerβs is not fully understood, but the Frick team is working on a hypothesis.
βWe think the reason is that E4 doesnβt do as good a job of clearing lipids and carrying them into cells as E3 and E2 do,β Frick said.
Thatβs important because both the hormone estrogen and amyloid, a toxic protein that builds up in the Alzheimerβs brain, are lipids, she said.
Many women are reluctant to take hormone therapy, whether it be for memory protection or to ease bothersome menopausal symptoms, because estrogen therapy can increase the risk of breast or uterine cancer and cardiovascular disease for some people. With colleagues from Concordia University Wisconsin and Marquette University, Frick formed the startup Estrigenix Therapeutics, Inc., with the goal of developing drug compounds that provide the benefits of estrogens without harmful side effects.
Her research team will be testing one of Estrigenixβs compounds with this funding, which may provide a new avenue for developing treatments that reduce Alzheimerβs risk in women of multiple APOE variants.
The Alzheimerβs Association is the largest nonprofit funder of Alzheimerβs research in the world, investing over $310 million in more than 950 projects in 48 countries.
By University Relations