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A groundbreaking study from UCLA Health has revealed a genetic mechanism that may explain why women are far more susceptible to Alzheimer’s disease and multiple sclerosis (MS) than men. The research, published in Science Translational Medicine in October 2025, identifies a gene on the X chromosome—called Kdm6a—as a key driver of inflammation in the female brain, potentially opening new doors to sex-specific treatments for neurodegenerative diseases .
Understanding the Discovery
The UCLA team, led by neurologist Dr. Rhonda Voskuhl, head of the Multiple Sclerosis Program at UCLA Health, found that women’s two X chromosomes result in a “double dose” of gene activity that amplifies brain inflammation. This inflammation, when chronic, is a key contributor to neurodegenerative conditions such as Alzheimer’s and multiple sclerosis .
Using a mouse model of MS, the researchers discovered that turning off the Kdm6a gene significantly reduced neuroinflammation and related brain damage in female mice. The same intervention, however, showed little effect in males. “This is consistent with there being ‘more to block’ in females due to having two copies of the X-linked gene,” explained Dr. Voskuhl. “It also clarifies why women are more likely to develop MS and Alzheimer’s disease than men” .
The Mechanism Behind Sex-Based Risk Differences
Unlike autosomal chromosomes, X chromosomes carry many immune and neurological genes, including those influencing the function of microglia, the immune cells that protect brain tissue. Because females possess two X chromosomes—compared to a single one in males—the expression of inflammatory genes can become amplified when regulatory mechanisms fail.
In this study, the gene Kdm6a was shown to ramp up inflammatory signaling in microglia, which in turn promotes neurodegeneration. Deactivating Kdm6a, either genetically or pharmacologically, restored microglial balance and prevented the inflammation-driven damage observed in female brains .
Metformin’s New Potential
The researchers tested whether metformin, a widely used diabetes medication, could moderate the inflammatory effects of Kdm6a. Metformin was found to suppress the protein linked to this gene, reducing neuroinflammation in female mice and improving disease outcomes. However, the same effect was “almost undetectable in males,” suggesting that treatments targeting this mechanism may need to be tailored specifically for women .
Dr. Voskuhl noted that “women may respond differently to metformin treatment than men,” reinforcing the emerging understanding that effective neurological disease therapies should account for biological sex differences .
Hormones, Menopause, and Brain Health
Dr. Voskuhl’s findings also shed light on the relationship between menopause, estrogen loss, and brain inflammation. Estrogen is known to have neuroprotective and anti-inflammatory properties. During a woman’s reproductive years, estrogen helps counterbalance the pro-inflammatory signals driven by X-linked genes.
However, as estrogen levels decline during menopause, this protection diminishes, exposing the brain to greater inflammatory stress. “Sex chromosomes and sex hormones achieve a balance through evolution,” Voskuhl explained. “As women age, menopause causes loss of estrogen, unleashing the proinflammatory and neurodegenerative effects of this X chromosome gene in brain immune cells” .
These findings may also help explain why about two-thirds of menopausal women report experiencing “brain fog” or cognitive sluggishness during this transition, providing new insight into the neurobiological factors underlying these symptoms .
Expert Commentary
Dr. Emily Reardon, a neurologist at the Mayo Clinic not involved in the study, called the discovery “a major advance in understanding sex-linked vulnerability in neurodegenerative disease.” She elaborated that “identifying a gene that bridges inflammation, aging, and hormonal regulation is critical for developing personalized therapies for women’s brain health.”
Similarly, Dr. Jae-Min Liu, professor of neuroimmunology at Stanford University, emphasized that this study reinforces the urgent need for sex-specific research in neurology. “Historically, most neurodegenerative disease models have been male-centric,” said Liu. “This research underscores how overlooking sex differences can mask critical mechanisms of disease.”
Implications for Treatment and Prevention
This research opens multiple new avenues for clinical innovation. First, estrogen-based therapeutics that target the brain could help restore balance in postmenopausal women, potentially delaying or preventing neurodegenerative decline. Second, repurposing metformin for neuroinflammatory conditions may offer a cost-effective preventive therapy for women at elevated risk.
However, researchers caution that these findings, while promising, are still in the preclinical stage. Studies in humans are necessary to confirm whether these mouse-model results can be replicated and safely translated to patients. “We’re still uncovering how much of this effect can be influenced by gene-environment interactions, lifestyle factors, and overall metabolic health,” Dr. Liu added.
Limitations and Future Research
Although this study provides strong evidence for the role of Kdm6a in driving female neuroinflammation, experts stress the need for longer-term, human-based studies. Genetic diversity, hormonal history, and individual immune responses may all modulate the gene’s impact.
Future clinical trials could test the neuroprotective benefits of metformin and estrogen-modulating drugs among postmenopausal women at high risk of Alzheimer’s or MS. Such research could lead to precision medicine approaches that tailor treatment protocols based on genetic and hormonal profiles.
Public Health Perspective
Women represent nearly two-thirds of Alzheimer’s patients worldwide and are diagnosed with multiple sclerosis two to three times more frequently than men, according to the World Health Organization and the National Multiple Sclerosis Society. A deeper understanding of the genetic and hormonal factors that drive these disparities may guide better prevention, early detection, and intervention strategies.
Public health experts say the study also underscores the importance of inclusive research practices that represent both sexes in neurological and aging studies. “Understanding sex-based biology is not just a matter of fairness—it’s a matter of scientific accuracy,” noted Dr. Reardon.
Medical Disclaimer
“Medical Disclaimer: This article is for informational purposes only and should not be considered medical advice. Always consult with qualified healthcare professionals before making any health-related decisions or changes to your treatment plan. The information presented here is based on current research and expert opinions, which may evolve as new evidence emerges.”
References
- https://www.news-medical.net/news/20251015/Discovery-explains-why-women-face-higher-risk-of-Alzheimere28099s-and-multiple-sclerosis.aspx#:~:text=Because%20females%20have%20two%20X,Alzheimer’s%20disease%20and%20multiple%20sclerosis.
