Brain cells that normally help protect the brain may play an unexpected role in cognitive decline as we grow older. Scientists have discovered that cells responsible for maintaining the protective coating around nerve fibers can become dysfunctional with age, potentially contributing to the gradual loss of memory and thinking abilities.
The research, published in Nature Medicine, challenges the long-held belief that these cells are always beneficial. By examining human brain tissue and conducting experiments in mice, researchers found evidence that problems with these normally supportive cells can damage nerve fibers and interfere with cognitive function.
The discovery also points to a possible new approach for protecting the aging brain. Drugs that act on the biological pathway involved are already being used to treat other neurological conditions, raising hopes that existing treatments could eventually be adapted to combat age-related cognitive decline.
Scientists Discover Changes in the Aging Brain
The study was led by researchers from the University of Edinburgh and the UK Dementia Research Institute, who investigated how changes in the brain relate to declining cognitive abilities later in life.
Their research focused on the Lothian Birth Cohort 1936, a group of people whose cognitive abilities have been tracked from childhood into old age. This unusually extensive record allowed scientists to investigate how thinking and memory changed over decades.
Between ages 70 and 82, participants underwent assessments measuring memory, the speed at which they processed information, and their ability to understand spatial relationships.
Of the 1,091 people enrolled in the cohort, 866 completed additional cognitive testing after age 70. Nearly everyone experienced at least some decline, but the rate varied considerably. These differences gave researchers an opportunity to investigate what might distinguish brains experiencing faster deterioration from those aging more gradually.
When scientists examined brain tissue collected after death from a subset of participants, they discovered a striking pattern. Individuals who had experienced greater cognitive decline tended to have fewer large nerve fibers, along with an abnormal buildup of unhealthy myelin.
Myelin is the protective coating that surrounds nerve fibers, helping electrical signals travel efficiently through the brain. Although this insulation is essential for normal brain function, the findings suggest that excessive or abnormal myelin may become part of the problem.
The changes were especially pronounced around the large nerve fibers that remained. Importantly, these abnormalities were associated with how quickly cognitive abilities declined, rather than how well someone performed on cognitive tests at a particular age.
A Protective Brain Cell May Have a Hidden Weakness
To understand what might be causing these changes, the researchers turned their attention to oligodendrocytes, specialized brain cells responsible for producing and maintaining myelin.
Oligodendrocytes have traditionally been regarded as beneficial because they help keep nerve fibers insulated and functioning properly. However, the new findings suggest that these cells can become dysfunctional during aging and may contribute to the very problems they normally help prevent.
The researchers discovered that people with more severe cognitive decline had lower levels of a protein called NRF2 inside their oligodendrocytes.
NRF2 plays an important protective role in cells by regulating hundreds of genes involved in defending against damage and maintaining normal cellular function. When its activity decreases, cells may become less capable of protecting themselves and performing their usual jobs.
To investigate whether this protein was directly involved in the brain changes, the team conducted experiments in mice.
When researchers specifically reduced NRF2 in oligodendrocytes, the animals developed excessive myelin and lost large nerve fibers, closely resembling the abnormalities observed in human brain tissue. The mice also showed reduced improvements in cognitive performance as they aged.
These experiments provided evidence that declining NRF2 activity can directly disrupt oligodendrocyte function, potentially triggering changes in myelin and nerve fibers that contribute to cognitive decline.
Existing Drugs Could Offer a New Treatment Strategy
The findings may have important implications for developing treatments that help preserve cognitive abilities in older adults.
One particularly promising aspect is that the NRF2 pathway is already a target of medications used for other conditions, including a drug prescribed to treat multiple sclerosis (MS).
Previous studies have found that increasing NRF2 activity can improve cognitive function in people with MS. That raises the possibility that medications acting on the same pathway might eventually be repurposed to address oligodendrocyte dysfunction and age-related cognitive decline.
Although further research is needed to determine whether such treatments would benefit older adults experiencing cognitive decline, the discovery identifies a potentially valuable therapeutic target.
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.”
A New Understanding of Cognitive Decline
Beyond its potential medical applications, the research changes how scientists understand the role of oligodendrocytes in the aging brain.
Rather than simply providing support for healthy nerve function throughout life, these cells appear capable of becoming dysfunctional and contributing to cognitive problems.
Georgina Craig, the study’s first author and a 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 findings suggest that maintaining healthy oligodendrocyte function could become an important strategy for protecting memory and thinking abilities as people grow older.
Published in Nature Medicine, the study was funded by the UKRI Medical Research Council (MRC) and the Canadian Institutes of Health Research (CIHR). The research also involved scientists from the University of Edinburgh’s Lothian Birth Cohort studies and Northwestern University.
