Study identifies protein markers that may explain why MS affects women three times more

Nearly three out of every four people living with multiple sclerosis are women. Among the 2.9 million people worldwide carrying this autoimmune disease, that disparity has long puzzled researchers. Why women bear such a disproportionate burden remains largely unexplained—but a small study from the University of Colorado Anschutz Medical Campus has begun to sketch an answer.

The researchers examined cerebrospinal fluid from three women diagnosed with MS and three women without the disease, all of similar age. Cerebrospinal fluid is the clear liquid that surrounds and cushions the brain and spinal cord, making it a window into what happens in the central nervous system. When they analyzed the proteins in these samples, they found more than 100 that differed between the two groups. Seventy-two proteins appeared in higher concentrations in women with MS; forty-six appeared in lower concentrations.

The elevated proteins told a story of immune activation. Several were linked to microglia, cells that clear away cellular debris, and macrophages, which destroy harmful invaders. The proteins that were reduced painted a different picture—many were associated with neurogenesis and neuron repair, the processes by which the brain generates new nerve cells and maintains existing ones. Multiple sclerosis itself is characterized by damage to myelin, the protective coating around nerve fibers. The implication is stark: in women with MS, the immune system appears to be ramped up while the brain's capacity to repair itself appears diminished.

Kimberley Bruce, an endocrinologist on the research team, noted that sex differences appear across many neurological diseases. Alzheimer's disease and MS strike women more often; Parkinson's disease strikes men more often. Understanding why could unlock insights into how these diseases actually work. "If we understand sex differences in more detail," Bruce said, "we can probably learn a lot about the underlying mechanisms driving these diseases."

The researchers suspect hormones are playing a central role, particularly for women in their thirties and forties—the very years when women receive MS diagnoses at three times the rate men do, and when pregnancies and menstrual cycle changes occur. One protein they identified was sex hormone-binding globulin, or SHBG, which binds to estrogen and testosterone. When SHBG levels are high, it sequesters these hormones, leaving less available to cells and tissues. Since sex hormones are thought to regulate immune activity in the brain, this mechanism could help explain why immune changes in MS might differ between women and men.

Bruce emphasized that these are preliminary hypotheses drawn from a very small sample. The findings need testing on larger groups and must be understood within the broader context of what researchers already know about MS and how it develops. The disease is complex, shaped by multiple distinct factors. But the protein markers identified here offer concrete targets for future investigation—and potentially for future drugs. Some of these proteins might one day be controlled with medication to help prevent or manage MS. The path forward, Bruce suggested, will require different therapies tailored to different factors, moving toward treatments designed for individual patients rather than a one-size-fits-all approach.