Faulty myelin-making brain cells may help drive cognitive decline with age

A rare combination of lifelong cognitive tracking, postmortem brain analysis, and targeted mouse experiments reveals unexpected changes in the cells that maintain the brain’s white matter.

A recent study published in the journal Nature Medicine suggests that dysfunction of oligodendrocytes, or brain cells that form myelin, may contribute to age-related cognitive decline in humans. The researchers observed smaller, degenerating axons with thicker myelin sheaths in individuals with greater cognitive decline, whereas larger mitochondria were more strongly associated with aging than with the severity of cognitive decline. They then performed animal experiments to test whether reduced oligodendrocyte NRF2 could reproduce aspects of the human pathology. In mice, conditionally deleting the gene encoding nuclear factor erythroid 2-related factor 2 (NRF2) from oligodendrocytes also produced comparable alterations in axon size and myelin thickness and reduced cognitive improvement over time.

Together with the human data, these observations suggest that increased oligodendrocyte density, reduced NRF2 expression, and damage to myelinated axons may offer valuable clues to the cellular changes underlying cognitive impairment. If confirmed in larger, more diverse human studies, these findings could help identify new ways to protect brain health during aging.

Cognitive processes deteriorate gradually with age, which may lead to memory-related difficulties and limit older individuals' ability to perform everyday tasks. Intervention strategies designed to alter molecular pathways associated with biological aging could potentially help slow or mitigate cognitive decline. While magnetic resonance imaging (MRI) scans have demonstrated abnormalities in the white matter of older individuals with cognitive impairment, corresponding changes occurring at the cellular level remain poorly understood.