Oligodendrocyte dysfunction in human age-related cognitive decline
Cognitive decline in aging impacts quality of life, for which therapeutic interventions are lacking. Why some individuals experience more severe cognitive decline with aging is unclear. Here we uncover a role for the brain's myelin-forming cells-oligodendrocytes-in explaining this variance. By investigating neuropathological and transcriptomic changes in human white matter associated with individual rates of cognitive decline in aging, we find that worse cognitive trajectories unexpectedly associate with smaller myelinated axon size, thicker myelin and more oligodendrocytes with downregulation of NRF2. Aged oligodendrocyte-specific NRF2-knockout mice showed attenuated cognitive improvement over time and mirrored the white matter pathology of human cognitive decline in aging. These findings place the oligodendrocyte as a contributor to cognitive decline and highlight the NRF2 pathway as a therapeutic target to preserve cognition in human aging.
Authors
- Georgina A. Craig (ORCID: https://orcid.org/0000-0003-3104-210X)
- Alana Hoffmann (ORCID: https://orcid.org/0000-0002-5476-1038)
- Keon Arbabi (ORCID: https://orcid.org/0000-0003-3219-8835)
- Emeric Merour (ORCID: https://orcid.org/0000-0002-3205-4164)
- Andrea Corsinotti (ORCID: https://orcid.org/0000-0003-4481-0999)
- Anna Williams (ORCID: https://orcid.org/0000-0002-6329-382X)
- Simon R. Cox (ORCID: https://orcid.org/0000-0003-4036-3642)
- Shreejoy J. Tripathy (ORCID: https://orcid.org/0000-0002-1007-9061)
- Janie Corley (ORCID: https://orcid.org/0000-0002-7551-1871)
- Tara L. Spires‐Jones (ORCID: https://orcid.org/0000-0003-2530-0598)
- Luise A. Seeker (ORCID: https://orcid.org/0000-0001-6375-6372)
- Véronique E. Miron (ORCID: https://orcid.org/0000-0003-1738-0647)
- Jessica Thapar
- Brian Popko (ORCID: https://orcid.org/0000-0001-9948-2553)
- Stephen Mitchell
- Lu O. Sun
- Jamie Rose
- Annette J. Haughian
- Colin Smith
- Susan D. Shenkin
Institutions
- Northwestern University (US)
- St. Michael's Hospital (CA)
- NHS Lothian (GB)
- Centre for Addiction and Mental Health (CA)
- University of Toronto (CA)
- St Michael’s Hospital (IE)
- MRC Centre for Regenerative Medicine (GB)
- Public Health Ontario (CA)
- UK Dementia Research Institute (GB)
- Wellcome Centre for Cell Biology (GB)
- Unity Health Toronto
- The University of Texas Southwestern Medical Center (US)
- Stanford University (US)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Medicine
- Published
- 2026-08-25
- DOI
- https://doi.org/10.1038/s41591-026-04608-y
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00