NRF2 Decline in Oligodendrocytes Accelerates Myelin Abnormalities and Cognitive Loss After Age 70

The team combined longitudinal cognitive data from 866 cohort members with post-mortem histology from a subset and targeted mouse experiments. They quantified large-caliber axons, myelin thickness, and NRF2 protein specifically within oligodendrocytes, then knocked down NRF2 selectively in mouse oligodendrocytes to test causality. Greater NRF2 loss predicted both excess myelin accumulation around remaining large fibers and steeper drops in processing speed and spatial reasoning, independent of baseline performance. This reframes oligodendrocytes as active contributors to decline rather than passive bystanders and identifies a druggable pathway already targeted in multiple sclerosis. Existing NRF2 modulators could be repurposed, but only if trials stratify participants by myelin imaging and cognitive trajectory rather than age alone.