A recent study published in Science Translational Medicine, has identified a gene on the X chromosome that drives inflammation in the female brain potentially explaining why women are disproportionately affected by neurological conditions such as Alzheimer’s disease and multiple sclerosis (MS). Researchers from UCLA Health Sciences used a mouse model of multiple sclerosis to study a gene called Kdm6a, located on the X chromosome. Females, who carry two X chromosomes compared to one in males, receive a “double dose” of the gene’s inflammatory effect in brain immune cells known as microglia. This heightened inflammation is known to contribute to aging, Alzheimer’s disease, and MS. First author Dr. Yuichiro Itoh of the Voskuhl Lab deactivated Kdm6a in microglia cells. This genetic "knockout" caused the inflammatory molecules to shift into a resting state, significantly improving MS-like symptoms in female mice. The team also tested a pharmacological “knockdown” using metformin, a diabetes drug under investigation for anti-aging properties. Again, the treatment significantly reduced inflammation in females but had little effect on males. “This is consistent with there being 'more to block' in females due to having two copies of the X-linked gene,” said Dr. Rhonda Voskuhl, lead author and director of the Multiple Sclerosis Program at UCLA Health, noting that these differences could impact how women respond to treatments like metformin. The study also offers a compelling explanation for brain fog in menopausal women, linking the loss of estrogen, an anti-inflammatory hormone, to increased activity of the proinflammatory X-linked gene. According to Voskuhl, targeting brain-specific estrogens may help restore the balance and protect women’s brains during aging. Reference:Itoh, Y., et al. (2025). Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles. Science Translational Medicine. doi.org/10.1126/scitranslmed.adq3401