Myelin-making brain cells may actively drive age-related cognitive decline, study finds

Brain cells long regarded as passive support staff for the nervous system may themselves drive the mental decline that comes with age, according to a study published Tuesday in Nature Medicine. Researchers at the University of Edinburgh and the UK Dementia Research Institute found that oligodendrocytes, the cells that wrap nerve fibers in an insulating coat called myelin, can turn dysfunctional as people grow older and appear to actively contribute to the loss of memory and processing speed that many people experience in later life.

The finding challenges a decades-old assumption in neuroscience. Oligodendrocytes have generally been treated as a kind of biological infrastructure: cells that build and maintain myelin so that electrical signals can travel efficiently along neurons, but that otherwise play no active role in disease. The new study argues that assumption needs revising, at least where cognitive aging is concerned.

What the researchers found

The team drew on the Lothian Birth Cohort 1936, a long-running Scottish study that has tracked the same group of people since they sat an intelligence test as eleven-year-olds. Of the 1,091 participants in the cohort, 866 underwent repeated cognitive testing after age 70, covering memory, processing speed and spatial skills through age 82. Nearly all of them showed some degree of decline over that period, but the rate varied widely from person to person.

Examining brain tissue and imaging data from cohort members, the researchers found that those with the steepest cognitive decline had fewer large-diameter nerve fibers, the fibers most responsible for fast signal transmission, and an excess of abnormal, poorly structured myelin wrapped around the large fibers that remained. The common thread across these changes was a protein called NRF2, which oligodendrocytes rely on to manage cellular stress. People with more severe cognitive decline had markedly lower levels of NRF2 in their oligodendrocytes.

To test whether the association was causal rather than coincidental, the researchers turned to mice, genetically reducing NRF2 specifically within oligodendrocytes. The animals developed the same signature of excess, disorganized myelin seen in the human tissue, and their performance on cognitive tasks declined. That experiment, the authors say, indicates the myelin abnormalities are not simply a byproduct of an aging brain but an active contributor to its decline.

A population already growing older

The stakes attached to the finding are large. The World Health Organization estimates that more than 57 million people worldwide are living with dementia, a figure it projects will more than double by 2050 as populations age. Cognitive decline that falls short of a dementia diagnosis is far more widespread still, affecting a large share of people who live into their eighties and beyond, with no approved treatment that reliably slows the process.

Myelin biology has traditionally taken a back seat to the two hallmarks most associated with Alzheimer's disease, amyloid plaques and tau tangles, in the search for treatments. The Edinburgh-led team's work adds to a smaller but growing body of research suggesting that white matter, the myelin-rich tissue that carries signals between brain regions, deteriorates in ways that are not simply downstream of those better-known pathologies but may independently shape how much cognitive function a person retains.

• 1,091 participants in the Lothian Birth Cohort 1936, with 866 followed through repeated cognitive testing from age 70 to 82
• Steeper decline linked to fewer large nerve fibers and excess, poorly structured myelin around the fibers that remained
• Lower NRF2 protein levels in oligodendrocytes tracked with more severe decline in the human data
• Reducing NRF2 in oligodendrocytes of mice reproduced the myelin abnormality and impaired the animals' cognitive performance

Reaction and who the finding affects

Georgina Craig, the study's first author and a postdoctoral fellow at St Michael's Hospital in Toronto, said the results overturn a long-held view of what these cells do in an aging brain.

"This study has fundamentally shifted how we think about these brain cells in ageing. We have always considered oligodendrocytes as purely beneficial, yet here we surprisingly find that they can become dysfunctional and contribute to cognitive impairment in ageing."

Veronique Miron, honorary chair at the UK Dementia Research Institute's Edinburgh centre and senior author on the paper, framed the discovery as opening a route toward treatments that do not currently exist. She and Craig hold joint appointments spanning Edinburgh and Toronto's Keenan Research Centre, where much of the mouse work was carried out. "As the prevalence of cognitive decline is rising with an ageing 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 ageing," Miron said in comments distributed through the university's press office.

The research does not point to an imminent treatment. What it offers instead is a specific molecular target, NRF2 signaling within oligodendrocytes, that other laboratories can now test as a lever for intervention, whether through drugs that support the pathway or approaches that clear away the dysfunctional cells. Because the underlying cohort data come from people who were cognitively healthy enough to be followed for years rather than patients already diagnosed with dementia, the findings speak most directly to the far larger population of older adults experiencing the ordinary, gradual cognitive slowing that accompanies aging rather than a specific neurodegenerative disease.

What happens next

The immediate next step, according to the researchers, is to determine whether restoring NRF2 activity in oligodendrocytes, or otherwise correcting the myelin abnormalities they produce, can slow or reverse cognitive decline in animal models before any such approach could be considered for people. The team also plans to examine whether the same NRF2-linked pattern appears in people with diagnosed dementia, not only those experiencing typical age-related decline, which would help clarify how directly the mechanism bears on diseases such as Alzheimer's.

The work was funded by the UK Research and Innovation Medical Research Council and the Canadian Institutes of Health Research, and depended on the decades of data collection behind the Lothian Birth Cohort 1936, a resource the UK Dementia Research Institute and Edinburgh researchers have drawn on repeatedly to link biological measurements to real-world cognitive trajectories. Independent replication in other aging cohorts, and confirmation that intervening in the pathway produces a measurable benefit rather than simply a biological marker, will determine whether the finding leads anywhere close to a treatment.