A study found that people with more severe cognitive decline had changes to nerve fibres and myelin – the protective coating around nerve fibres that helps messages travel efficiently through the brain.
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 in later life.
Brain ageing
Researchers from the University of Edinburgh and UK Dementia Research Institute initially analysed 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.
Myelin damage
When looking directly at post mortem brain tissue from a subset of participants, they found that more severe cognitive decline was associated with fewer large nerve fibres and excess, unhealthy myelin, particularly around the larger fibres that remained.
These changes were linked to the rate of cognitive decline rather than a person’s cognitive ability at any particular time.
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 fibres. It also impaired improvements in cognitive performance as the mice aged.
Drug repurposing
The findings suggest that reduced NRF2 activity can drive oligodendrocyte dysfunction, contributing to changes in myelin and nerve fibres associated with cognitive decline during ageing.
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 ageing.