NRF2 dysfunction in oligodendrocytes emerges as a driver of cognitive aging

Researchers have identified a precise molecular mechanism underlying variable cognitive decline in aging: NRF2 pathway downregulation in oligodendrocytes, the brain cells that maintain myelin insulation around neuronal axons. While prior studies established that learning requires new oligodendrocyte generation and that aging correlates with oligodendrocyte loss and cognitive impairment, this work reveals the picture is more nuanced. The team compared neuropathological and transcriptomic changes in white matter across humans with different cognitive trajectories, discovering that patients with steeper cognitive decline possessed smaller myelinated axons, thicker myelin, and oligodendrocytes with reduced NRF2 expression. Aged mice engineered with NRF2 deletion specifically in oligodendrocytes exhibited attenuated cognitive improvement and mirrored the white matter pathology observed in cognitively declining humans. These findings establish the NRF2 pathway as a concrete therapeutic target for preserving cognition during aging, suggesting intervention strategies beyond traditional remyelination approaches and offering a molecular mechanism to explain individual differences in how we age cognitively.