Age-related oligodendrocyte dysfunction may contribute to cognitive decline by disrupting myelin and large nerve fibers.
Myelin is essential for fast communication in the brain, forming a protective coating around nerve fibers so electrical signals can travel efficiently. But the cells that produce this insulation, called oligodendrocytes, may become dysfunctional with age and actively contribute to cognitive decline.
Researchers found that people whose cognition declined more severely had fewer large nerve fibers and abnormal increases in myelin. Experiments in mice strengthened the connection by showing that disrupting oligodendrocytes produced similar changes and impaired cognitive performance.
The findings challenge the long-held view that oligodendrocytes are always beneficial to brain health. They also point toward the possibility of future treatments aimed at correcting oligodendrocyte dysfunction to preserve cognition in later life.
Brain changes tracked faster cognitive decline
Researchers at the University of Edinburgh and UK Dementia Research Institute investigated brain tissue from members of the Lothian Birth Cohort 1936, whose cognitive abilities have been followed from childhood into older age.
Between ages 70 and 82, participants completed tests of memory, processing speed, and spatial skills. Of the 1,091 people in the cohort, 866 returned for cognitive testing after age 70.
Nearly all showed some degree of decline, giving the researchers an opportunity to compare brain tissue from people whose cognition changed faster or slower than average.
Post-mortem tissue from a subset of participants revealed a clear pattern. Faster cognitive decline was associated with fewer large nerve fibers and excess unhealthy myelin, especially surrounding the larger fibers that remained.
These differences reflected the rate at which cognition changed over time rather than a person’s cognitive ability at any single point.
NRF2 emerged as a possible driver
The researchers then looked for a molecular explanation and found that people with more severe cognitive decline had lower amounts of NRF2 in their oligodendrocytes. NRF2 is a protein that regulates hundreds of genes involved in protecting cells from damage and maintaining normal cellular function.
To test whether reduced NRF2 could help produce the same changes, the researchers specifically lowered NRF2 in oligodendrocytes in mice. The animals developed excess myelin and lost large nerve fibers. Their expected improvements in cognitive performance with age were also impaired.
The results suggest that reduced NRF2 activity can drive oligodendrocytes into a dysfunctional state, contributing to changes in myelin and nerve fibers associated with cognitive decline during aging.
An existing pathway suggests a treatment route
NRF2 is already targeted by existing medications, including a drug used to treat multiple sclerosis (MS). Earlier research has shown that activating NRF2 can improve cognitive function in people with MS, raising the possibility that treatments targeting this pathway might eventually be repurposed for oligodendrocyte dysfunction and cognitive decline in aging.
Veronique Miron, MRC Senior Non-Clinical Fellow and UK Dementia Research Institute Group Leader at the University of Edinburgh and St. Michael’s Hospital, part of Unity Health Toronto, said: “As the prevalence of cognitive decline is rising with an aging population and no current treatments exist, we are excited about this work as it points to a potential strategy for new therapeutic strategies to preserve cognitive ability in aging.”
Georgina Craig, first author of the study and Postdoctoral Fellow at St Michael’s Hospital in Toronto and the UK Dementia Research Institute, said: “This study has fundamentally shifted how we think about these brain cells in aging. We have always considered oligodendrocytes as purely beneficial, yet here we surprisingly find that they can become dysfunctional and contribute to cognitive impairment in aging.”
Reference: “Oligodendrocyte dysfunction in human age-related cognitive decline” by Georgina A. Craig, Emeric Merour, Luise A. Seeker, Annette J. Haughian, Keon Arbabi, Jamie Rose, Alana Hoffmann, Jessica Thapar, Andrea Corsinotti, Stephen Mitchell, Janie Corley, Susan D. Shenkin, Colin Smith, Tara L. Spires-Jones, Lu O. Sun, Simon R. Cox, Anna Williams, Shreejoy J. Tripathy, Brian Popko and Véronique E. Miron, 25 August 2026, Nature Medicine.
DOI: 10.1038/s41591-026-04608-y
Funded by the UKRI Medical Research Council (MRC) and the Canadian Institutes of Health Research (CIHR)
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