Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer's disease

  • Nat Med. 2025 Jun;31(6):2044-2053. doi: 10.1038/s41591-025-03617-7.
Kanta Horie  #  1  2  3 ,  Gemma Salvadó  #  4 ,  Rama K Koppisetti  5  6 ,  Shorena Janelidze  4 ,  Nicolas R Barthélemy  5  7 ,  Yingxin He  5  7 ,  Chihiro Sato  5  7 ,  Brian A Gordon  8  9 ,  Hong Jiang  7 ,  Tammie L S Benzinger  8  9  10 ,  Erik Stomrud  4  11 ,  David M Holtzman  7  9  10 ,  Niklas Mattsson-Carlgren  4  11  12 ,  John C Morris  7  9 ,  Sebastian Palmqvist  4  11 ,  Rik Ossenkoppele  4  13  14 ,  Suzanne E Schindler  7  9 ,  Oskar Hansson  #  15 ,  Randall J Bateman  #  16  17  18  19
Affiliations
  • 1. The Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 2. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 3. Eisai Inc., Nutley, NJ, USA. [email protected].
  • 4. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
  • 5. The Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, USA.
  • 6. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • 7. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • 8. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
  • 9. Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
  • 10. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
  • 11. Memory Clinic, Skåne University Hospital, Malmö, Sweden.
  • 12. Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.
  • 13. Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • 14. Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
  • 15. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. [email protected].
  • 16. The Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 17. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 18. Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 19. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • # Contributed equally.
PMID: 40164726 DOI: 10.1038/s41591-025-03617-7
Abstract

Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer's Disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts (n = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma eMTBR-tau243 showed strong associations with tau positron emission tomography binding (β = 0.72, R2 = 0.56) and cognitive performance (β = 0.60, R2 = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials.