Multiple sclerosis may quietly damage the brain for years before symptoms appear, and scientists can now see it coming.
By the time people seek medical care for multiple sclerosis (MS), the disease has often been harming the brain for years. Until recently, however, researchers did not know exactly which brain cells were affected first or when this damage actually began.
Blood Proteins Reveal the Earliest Attacks
Scientists at UC San Francisco have now gained new insight by examining thousands of proteins circulating in the blood. This approach has provided the clearest picture so far of when MS first attacks the myelin sheath, the protective layer that surrounds nerve fibers. The results show that the immune system starts targeting the brain much earlier than scientists previously believed.
The researchers tracked fragments left behind by these immune attacks in blood samples, along with molecular signals that guide immune cells to their targets. Together, these measurements allowed the team to map out the order of biological events that eventually lead to MS, something that had not been clearly defined before.
This breakthrough may open new paths for diagnosing multiple sclerosis — and could even make prevention possible in the future.
Myelin Damage Comes First
The findings show that MS initially damages the fatty myelin sheath. About a year later, signs of injury to the nerve fibers themselves become detectable.
Among the many immune signaling proteins that rose early in the disease process, one stood out. The protein IL-3 appears to play a key role during this silent stage, when the central nervous system is already experiencing significant damage, but patients still feel no symptoms. IL-3 is known to draw immune cells into the brain and spinal cord, where they attack nerve cells.
“We think our work opens numerous opportunities for diagnosing, monitoring, and possibility treating MS,” said Ahmed Abdelhak, MD, assistant professor of Neurology at UCSF and first and co-lead author of the study, published in Nature Medicine on Oct. 20. “It could be a game-changer for how we understand and manage this disease.”
Clues Found Years Before Diagnosis
To reach these conclusions, the researchers analyzed more than 5,000 proteins in blood samples from 134 people with MS, collected both before and after diagnosis. The samples came from the U.S. Department of Defense Serum Repository, which stores blood samples from service members when they apply to join the military. These samples can be studied decades later, after some individuals have gone on to develop MS.
Seven years before diagnosis, researchers detected a sharp increase in a protein called MOG, which stands for myelin oligodendrocyte glycoprotein. This protein signals damage to the insulating layer around nerve fibers. About one year after the MOG increase, levels of neurofilament light chain rose, indicating damage to the nerve fibers themselves.
During this same period, IL-3 and other immune-related proteins involved in directing immune responses also appeared in the blood.
Toward Earlier Detection and Prevention
Overall, the team identified roughly 50 proteins that signal an increased risk of developing MS in the future. They have filed a patent application for a diagnostic blood test based on the 21 most promising markers.
Ari Green, MD, chief of the Division of Neuroimmunology and Glial Biology in the UCSF Department of Neurology and senior author of the study, said the findings offer both hope for prevention and a clearer understanding of how MS symptoms eventually develop.
“We now know that MS starts way earlier than the clinical onset, creating the real possibility that we could someday prevent MS — or at least use our understanding to protect people from further injury.”
Reference: “Myelin injury precedes axonal injury and symptomatic onset in multiple sclerosis” by Ahmed Abdelhak, Gabriel Cerono, Fahime Sheikhzadeh, Adil Harroud, Kiarra Ning, Colin R. Zamecnik, Gavin M. Sowa, John Boscardin, Christian Cordano, Asritha Tubati, Camille Fouassier, Eric D. Chow, Refujia Gomez, Adam Santaniello, Kelsey C. Zorn, Jill A. Hollenbach, Jorge R. Oksenberg, Bruce A. C. Cree, Stephen L. Hauser, Jonah R. Chan, Sergio E. Baranzini, Mitchell T. Wallin, Michael R. Wilson and Ari J. Green, 20 October 2025, Nature Medicine.
DOI: 10.1038/s41591-025-04014-w
Authors: Other UCSF authors are Gabriel Cerono, MD, Kiarra Ning, John Boscardin, PhD, The UCSF ORIGINS Study, Christian Cordano, MD, PhD, Asritha Tubati, Camille Fouassier, Eric D. Chow, PhD, Refujia Gomez, Adam Santaniello, Kelsey C. Zorn, MHS, Jill A. Hollenbach, PhD, MPH, Jorge R. Oksenberg, PhD, Bruce A.C. Cree, MD, PhD, MAS, Stephen L. Hauser, MD, Jonah R. Chan, PhD, Sergio E. Baranzini, PhD, Michael R. Wilson, MD, and Ari J. Green, MD. For all authors, see the paper.
Funding: This work was funded in part by the Department of Defense (HT94252310499), the National Institutes of Health (R01 NS105741 R01AG062562 R01AG038791, 1S10OD028511-01, R35NS111644, the Valhalla Foundation, the National MS Society, the Westridge Foundation, the National Multiple Sclerosis Society (RFA-2104-37504, SI-2001-35751), the Water Cove Charitable Foundation, Tim and Laura O’Shaughnessy, and the Littera Family. For all funding and disclosures, see the paper.
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