Plasma p-tau217 and tau-PET predict future cognitive decline among cognitively unimpaired individuals: implications for clinical trials
Plasma p-tau217 and tau positron emission tomography (PET) are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In a head-to-head comparison study including nine cohorts and 1,474 individuals, we show that plasma p-tau217 and medial temporal lobe tau-PET signal display similar associations with cognitive decline on a global cognitive composite test (R<sup>2</sup><sub>PET</sub> = 0.34 versus R<sup>2</sup><sub>plasma</sub> = 0.33, P<sub>difference</sub> = 0.653) and with progression to mild cognitive impairment (hazard ratio (HR)<sub>PET</sub> = 1.61 (1.48-1.76) versus HR<sub>plasma</sub> = 1.57 (1.43-1.72), P<sub>difference</sub> = 0.322). Combined plasma and PET models were superior to the single-biomarker models (R<sup>2</sup> = 0.35, P < 0.01). Sequential selection using plasma phosphorylated tau at threonine 217 (p-tau217) and then tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 76% reduction when using plasma p-tau217 alone. Thus, plasma p-tau217 and tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use enhances screening efficiency for preclinical AD trials.
Authors
- Tammie L.S. Benzinger (ORCID: https://orcid.org/0000-0002-8114-0552)
- Vincent Doré (ORCID: https://orcid.org/0000-0002-8051-0558)
- Clifford R. Jack (ORCID: https://orcid.org/0000-0001-7916-622X)
- Joseph Therriault (ORCID: https://orcid.org/0000-0002-7826-4781)
- Alexa Pichet Binette (ORCID: https://orcid.org/0000-0001-5218-3337)
- Divya Bali (ORCID: https://orcid.org/0000-0003-3178-1586)
- James D. Doecke (ORCID: https://orcid.org/0000-0003-2863-0293)
- Randall John Bateman (ORCID: https://orcid.org/0000-0002-7729-1702)
- Christopher C. Rowe (ORCID: https://orcid.org/0000-0003-3910-2453)
- 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)
- Wiesje M. van der Flier (ORCID: https://orcid.org/0000-0001-8766-6224)
- Erin M. Jonaitis (ORCID: https://orcid.org/0009-0004-5091-8255)
- Emma M. Coomans (ORCID: https://orcid.org/0000-0002-4289-9101)
- Elsmarieke van de Giessen
- Azadeh Feizpour
- Ronald Carl Petersen (ORCID: https://orcid.org/0000-0002-8178-6601)
- Niklas Mattsson (ORCID: https://orcid.org/0000-0002-8885-7724)
- Nesrine Rahmouni (ORCID: https://orcid.org/0009-0004-3081-8468)
- Colin L. Masters (ORCID: https://orcid.org/0000-0003-3072-7940)
- Oskar Hansson (ORCID: https://orcid.org/0000-0001-8467-7286)
- Gemma Salvadó (ORCID: https://orcid.org/0000-0002-5210-9230)
- Charlotte Elisabeth Teunissen (ORCID: https://orcid.org/0000-0002-4061-0837)
- Suzanne E. Schindler (ORCID: https://orcid.org/0000-0002-1680-1465)
- Sylvia Villeneuve (ORCID: https://orcid.org/0000-0003-2338-0467)
- Shorena Janelidze (ORCID: https://orcid.org/0000-0003-2869-8378)
- Sterling C. Johnson (ORCID: https://orcid.org/0000-0002-8501-545X)
- Pedro Rosa‐Neto (ORCID: https://orcid.org/0000-0001-9116-1376)
- Linda Karlsson (ORCID: https://orcid.org/0000-0002-0630-772X)
- Heather J. Wiste (ORCID: https://orcid.org/0009-0002-8833-2693)
Institutions
- University of Wisconsin–Madison (US)
- The University of Melbourne (AU)
- Malmö University (SE)
- Lund University (SE)
- Washington University in St. Louis (US)
- Florey Institute of Neuroscience and Mental Health (AU)
- Douglas Mental Health University Institute (CA)
- Amsterdam Neuroscience (NL)
- Mayo Clinic in Arizona (US)
- Skåne University Hospital (SE)
- Australian e-Health Research Centre (AU)
- Mayo Clinic in Florida (US)
- Austin Health (AU)
- McGill University (CA)
- Vrije Universiteit Amsterdam (NL)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-03-28
- DOI
- https://doi.org/10.1038/s43587-025-00835-z
- Citations
- 57
- Primary Topic
- Dementia and Cognitive Impairment Research
- Type
- article
- Field-Weighted Citation Impact
- 83.86