Researchers analyzing cognitive trajectories and postmortem brain tissue from the Lothian Birth Cohort 1936 have found that dysfunction in oligodendrocytes—the brain cells responsible for producing myelin—may contribute to age-related cognitive decline in humans, according to a study published in Nature Medicine.
For decades, oligodendrocytes had a simple job description. They wrap nerve fibers in myelin, the fatty sheath that lets electrical signals travel quickly, and they were considered unambiguously helpful.
That narrative has shifted. A study published in Nature Medicine reveals that these support cells can become dysfunctional and contribute to cognitive impairment as humans age. The research combines lifelong cognitive tracking, postmortem brain analysis, and targeted mouse experiments to investigate cellular changes underlying cognitive impairment.
Inside the Lothian Birth Cohort 1936 Dataset
The human data driving this discovery rests on the Lothian Birth Cohort 1936. Participants in this group first took a general intelligence test in 1947 at a mean age of 11 years. Decades later, those participating in later-life assessments were followed from age 70 approximately every three years thereafter.
Out of 1,091 participants, 866 participated beyond wave 1 of follow-up testing after age 70. Researchers utilized standardized instruments like the Wechsler Adult Intelligence Scale-III and the Wechsler Memory Scale-III to evaluate cognition. Latent cognitive growth curve models revealed that nearly all participants showed cognitive decline beyond age 70, dropping at an average rate of −0.26 standard deviation g units per year.
When the scientific team examined donated postmortem brain tissue from a subset of these participants, they uncovered a counterintuitive biological signature. Individuals with greater cognitive decline exhibited smaller myelinated axons coupled with thicker myelin sheaths on axons exceeding 1.0 μm in diameter, alongside an increased density of oligodendrocytes.
The Cellular Machinery and NRF2 Deficiency
To understand why more insulating cells and thicker myelin correlated with worse cognitive outcomes, researchers looked at the physics of neural transmission. Roughly 85 percent of the variance in human nerve conduction speed is attributed to axon size and myelin thickness.
At the molecular level, the human tissue analysis pointed to nuclear factor erythroid 2-related factor 2 (NRF2), a protein that regulates hundreds of genes protecting cells from damage. Participants with more severe cognitive decline had a smaller proportion of oligodendrocytes expressing NRF2.
To test whether this protein deficit caused the pathology or merely accompanied it, researchers engineered mice with the NRF2-encoding gene conditionally deleted specifically within their oligodendrocytes. Evaluated through behavioral tests like the Morris water maze, control animals improved their performance by an average of about 58 percent over four days of testing. The knockout mice showed reduced cognitive improvement over time, and their brain tissue produced comparable alterations in axon size and myelin thickness to those seen in humans.
Georgina Craig, the study’s first author and a postdoctoral fellow at St Michael’s Hospital in Toronto and the UK Dementia Research Institute, stated that this study has fundamentally shifted how we think about these brain cells in aging, noting that while oligodendrocytes have always been considered purely beneficial, the researchers surprisingly found that they can become dysfunctional and contribute to cognitive impairment in aging.
Therapeutic Horizons and Unresolved Questions
The findings suggest that NRF2 could be explored in further studies to develop therapeutic strategies to protect brain health during aging.
