Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease
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, R<sup>2</sup> = 0.56) and cognitive performance (β = 0.60, R<sup>2</sup> = 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.
Authors
- Tammie L.S. Benzinger (ORCID: https://orcid.org/0000-0002-8114-0552)
- Randall John Bateman (ORCID: https://orcid.org/0000-0002-7729-1702)
- Chihiro Sato (ORCID: https://orcid.org/0000-0002-7639-8727)
- Sebastian Palmqvist (ORCID: https://orcid.org/0000-0002-9267-1930)
- Rik Ossenkoppele (ORCID: https://orcid.org/0000-0003-1584-7477)
- Erik Stomrud (ORCID: https://orcid.org/0000-0002-0841-5580)
- Yingxin He (ORCID: https://orcid.org/0000-0003-2543-4553)
- Niklas Mattsson (ORCID: https://orcid.org/0000-0002-8885-7724)
- Oskar Hansson (ORCID: https://orcid.org/0000-0001-8467-7286)
- Gemma Salvadó (ORCID: https://orcid.org/0000-0002-5210-9230)
- John C. Morris (ORCID: https://orcid.org/0000-0001-9820-5618)
- Nicolas R. Barthélemy (ORCID: https://orcid.org/0000-0003-4937-2860)
- Rama K. Koppisetti (ORCID: https://orcid.org/0000-0002-7539-4572)
- Suzanne E. Schindler (ORCID: https://orcid.org/0000-0002-1680-1465)
- Shorena Janelidze (ORCID: https://orcid.org/0000-0003-2869-8378)
- Kanta Horie (ORCID: https://orcid.org/0000-0001-7736-2614)
- David M. Holtzman (ORCID: https://orcid.org/0000-0002-3400-0856)
- Brian A. Gordon (ORCID: https://orcid.org/0000-0003-2109-2955)
- Hong Jiang (ORCID: https://orcid.org/0000-0001-6480-7469)
Institutions
- Lund University (SE)
- Washington University in St. Louis (US)
- Amsterdam Neuroscience (NL)
- Hope Center for Neurological Disorders (US)
- Skåne University Hospital (SE)
- Eisai (United States) (US)
- Eisai (Japan) (JP)
- Vrije Universiteit Amsterdam (NL)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-03-31
- DOI
- https://doi.org/10.1038/s41591-025-03617-7
- Citations
- 71
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 82.66
Funders
- National Institutes of Health