We’re (Finally) Learning More About the Female Brain
A new study has revealed a breakthrough in how we can develop new treatments for Alzheimer’s Disease. It’s built on something doctors have noticed in the clinic for decades, but until now, couldn’t explain.
Before I talk about this breakthrough, it’s essential to name two things we know about Alzheimer’s Disease. First, aging is a risk factor. Second, two thirds of Alzheimer’s Disease patients are women, and this remains true when comparing women and men who are age matched. In other words, the preponderance of Alzheimer’s Disease in women is not merely due to women living a few years longer.
Why are women more likely to have Alzheimer’s Disease? And what can we learn from other diseases to help us answer that first question? Two thirds of patients with multiple sclerosis (MS) are women. MS is an autoimmune and neurodegenerative disease that causes several disabilities, including cognitive disability. Notably, other autoimmune diseases also show a female preponderance, including lupus and rheumatoid arthritis.
The Clues Hidden in the Immune System
Females have two X chromosomes (XX) and males have one (XY). In models of MS and lupus, my lab at UCLA previously showed that having two X chromosomes in blood immune cells drives autoimmunity more in females, compared to having only one X chromosome gene in males. Other research has found that having two X chromosomes in blood immune cells likely plays a role in lupus.
While Alzheimer’s Disease is not considered an autoimmune disease affecting blood immune cells, there is a critical immune cell in the brain that is known to play a major role in Alzheimer’s Disease. It is named microglia.
A shared feature of Alzheimer’s Disease and MS is that the main immune cell in the brain (microglia) changes from a resting state to an activated, proinflammatory state. This immune cell is also activated during aging in otherwise healthy people. Activation of this brain immune cell can cause damage to nerve cells (neurons) and decrease their connections with each other (synapses). Brain regions eventually atrophy, and clinical symptoms occur in functions served by these regions. Activation of this brain immune cell is thought to drive Alzheimer’s Disease, MS, and brain aging.
A Breakthrough Finding
My team and I recently made a breakthrough discovery, which we published in the journal Science Translational Medicine on October 15. We asked if microglia differ in women versus men, and if so, is there a gene on the X chromosome in this brain immune cell that predisposes women to disease? We found that an X chromosome gene (KDM6A) was expressed higher in brain immune cells in women with MS compared to men with MS. Also, there were higher levels of inflammatory activation markers in women’s brain immune cells.
Then, we treated female mice with the MS-like disease. Some underwent selective deletion of the X chromosome gene within the brain immune cell so we could see what would happen. Deletion of this X chromosome gene in the brain immune cell reversed it back from an activated state to a resting state. Neuropathology was decreased, and clinical disease was ameliorated. We treated other female mice with an existing drug known to block the X chromosome protein (KDM6A), and it also ameliorated disease in females.
The takeaway: Both genetic “knock-out” and pharmacologic “knock-down” of this X chromosome gene halted brain inflammation and degeneration.
What was the drug that deactivated this brain immune cell? Metformin, which is used widely for diabetes and has shown anti-aging properties.
There are three relevant points about metformin you should know. First, it may work through other mechanisms, in addition to blocking actions of this X chromosome gene. Second, there is now a rationale to develop new drugs that are more specific, blocking only KDM6A, to reduce off-target side effects of metformin. Third, such treatments should be tested in disease models, then in people with MS, Alzheimer’s Disease, and brain aging.
Why This Matters for Women—and Men
You might wonder: What are the implications for treating men with a drug targeting this X chromosome gene?
In contrast to the protection induced in female mice by targeting the X chromosome gene, there was no protection in males. This is consistent with the paper’s findings that brain immune cells of men with MS did not have either high levels of the X gene expressed or activation markers. So, only women have high levels of the X chromosome gene driving brain immune cells toward activation and subsequent brain degeneration.
A key takeaway is that if a clinical trial were only done in men, the beneficial effect in women would have been missed. Also, in clinical trials that pool together women and men, a beneficial effect in women would be diluted out by no benefit in men. Therefore, the study of sex differences in neurological diseases can lead to novel brain protective treatments optimized for each sex, and future clinical trials need to be designed accordingly. This is particularly true in MS and Alzheimer’s Disease.
You might also wonder: Are sex differences in diseases caused only by sex chromosomes (XX vs XY) or can they also be due to sex hormones (estrogen vs testosterone)?
It is both. Estrogen and testosterone in women and men, respectively, have brain protective properties. However, brain protection depends on hormone type, dose, and timing. With respect to brain aging, the gradual waning of testosterone in men with andropause from ages 30 to 70 years contrasts with the relatively abrupt onset of menopause in women at mean age range 48-54 years. Women will be estrogen deficient for a third of their life, from their early 50s to mid-80s. “Brain fog” of menopause includes problems with cognitive domains like verbal and working memory, and there are abnormalities in the memory region of the brain (the hippocampus) on magnetic resonance imaging (MRI).
We’ve learned a lot about estrogen and the brain in MS. Women with MS report that menopause worsens their disabilities, including fatigue and cognition. Conversely, when MS women are pregnant with high levels of estriol, the estrogen unique to pregnancy, and estradiol, the estrogen of menstrual cycling, their MS is better. During the postpartum period, when estriol is completely gone and estradiol drops back down to cycling levels, their MS is worse. Basic research in MS models identified the brain cell and estrogen receptor that confers brain protection during estriol treatment, and clinical trials in women with MS showed cognitive improvement and less regional brain atrophy by MRI in women with MS who were treated for twelve months with oral estriol.
Findings in MS were then repurposed to otherwise healthy women with cognitive symptoms of menopause. Basic neuroscience research was done in the menopause model in female mice, and then findings transitioned to treatment of menopausal women using a hormone treatment designed for brain protection. It contains tailored estriol and progesterone, is patented by UCLA, and is now available nationwide through telemedicine from CleopatraRx. Early findings have been submitted for publication showing that treatment of otherwise healthy menopausal women for twelve months improves cognitive symptoms.
Overall, this is very good news! Discovery of factors that contribute to women being susceptible to MS, Alzheimer’s Disease, and menopause-related brain aging can lead to new treatments targeting these factors. Specifically, there is now scientific rationale to block the deleterious effects of an X chromosome gene (KDM6A) and maintain the protective effects of a sex hormone (estrogen) in the brains of women.
Rhonda Voskuhl, MD, is a professor of neurology, director of the UCLA MS Program, a faculty neurologist at the UCLA Comprehensive Menopause Center, and founder and inventor of CleopatraRx.
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