Brain cells that produce the protective coating around nerve fibers can become dysfunctional with age and may actively contribute to cognitive decline, according to new research.
A study found that people with more severe cognitive decline had changes to nerve fibers and myelin—the protective coating around nerve fibers that helps messages travel efficiently through the brain. The study is published in the journal Nature Medicine.
Experiments in mice showed that disrupting oligodendrocytes—the cells that produce myelin—also altered the coating and impaired cognitive performance.
Experts say the findings overturn the longstanding view that these cells are always supportive of healthy brain function and could pave the way for new treatments targeting oligodendrocyte dysfunction to help protect cognition later in life.
Tracking decline across decades
Researchers from the University of Edinburgh and UK Dementia Research Institute initially analyzed brain tissue from the Lothian Birth Cohort 1936, whose members have had their cognitive abilities assessed from childhood into older age.
Cognitive performance was measured from age 70 to 82 using tests covering memory, processing speed and spatial skills.
Of 1,091 people in the cohort, 866 had follow-up cognitive testing after age 70. Almost all experienced some degree of cognitive decline, allowing researchers to compare brain changes in people whose decline was faster or slower than average.
When looking directly at postmortem brain tissue from a subset of participants, they found that more severe cognitive decline was associated with fewer large nerve fibers and excess, unhealthy myelin, particularly around the larger fibers that remained.
These changes were linked to the rate of cognitive decline rather than a person’s cognitive ability at any particular time.
NRF2 loss points to mechanism
The researchers then found that people with more severe cognitive decline had reduced levels of the protein NRF2 in oligodendrocytes. NRF2 regulates hundreds of genes involved in protecting cells from damage and maintaining healthy cellular function.
Experiments in mice showed that reducing NRF2 specifically in oligodendrocytes caused excess myelin and reduced large nerve fibers. It also impaired age-related improvements in cognitive performance.
The findings suggest that reduced NRF2 activity can drive oligodendrocyte dysfunction, contributing to changes in myelin and nerve fibers associated with cognitive decline during aging.
Existing drugs may offer a lead
The NRF2 pathway is already targeted by drugs, including one that treats multiple sclerosis (MS). Previous research has shown that activating NRF2 can improve cognitive function in people with MS, raising the possibility that existing treatments could eventually be repurposed to target oligodendrocyte dysfunction and cognitive decline in aging.
Veronique Miron, MRC senior nonclinical 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.”
The study involved researchers from the University of Edinburgh’s Lothian Birth Cohort studies and Northwestern University. https://medicalxpress.com/news/2026-08-brain-cells-cognitive-decline.html
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