Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex

Tau positron emission tomography (PET) imaging allows in vivo detection of tau proteinopathy in Alzheimer's disease, which is associated with neurodegeneration and cognitive decline. Understanding how demographic, clinical and genetic factors relate to tau PET positivity will facilitate its use for clinical practice and research. Here we conducted an analysis of 42 cohorts worldwide (N = 12,048), including 7,394 cognitively unimpaired (CU) participants, 2,177 participants with mild cognitive impairment (MCI) and 2,477 participants with dementia. We found that from age 60 years to 80 years, tau PET positivity in a temporal composite region increased from 1.1% to 4.4% among CU amyloid-β (Aβ)-negative participants and from 17.4% to 22.2% among CU Aβ-positive participants. Across the same age span, tau PET positivity decreased from 68.0% to 52.9% in participants with MCI and from 91.5% to 74.6% in participants with dementia. Age, Aβ status, APOE ε4 carriership and female sex were all associated with a higher prevalence of tau PET positivity across groups. APOE ε4 carriership in CU individuals lowered the age at onset of both Aβ positivity and tau positivity by decades. Finally, we replicated these associations in an independent autopsy dataset (N = 5,072 from 3 cohorts).

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Publication Details

Journal
Nature Neuroscience
Published
2025-07-16
DOI
https://doi.org/10.1038/s41593-025-02000-6
Citations
22
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
Field-Weighted Citation Impact
32.37

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article

Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex

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Dementia and Cognitive Impairment Research
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Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex

Tammie L.S. Benzinger, Vincent Doré, Reisa A. Sperling, Xiaoxie Mao, Gérard N. Bischof, Clifford R. Jack, Maura Malpetti, Jun Pyo Kim, Joseph Therriault, Adam M. Brickman, Tobey J. Betthauser, José A. Luchsinger, Michael Rullmann, Renaud La Joie, Michel Bottlaender, Yuna Gu, Julien Lagarde, Shannon L. Risacher, Julie A. Schneider, Christopher C. Rowe, Sebastian Palmqvist, Rik Ossenkoppele, Erik Stomrud, James B. Rowe, Andrew J. Saykin, María C. Carrillo, Pieter Jelle Visser, Judes Poirier, Olof T. Strandberg, Patrick J. Lao, Howard Rosen, Wiesje M. van der Flier, Marie Sarazin, Sergey Shcherbinin, Henryk Barthel, Emma M. Coomans, Valentina Garibotto, Pierrick Bourgeat, Elsmarieke van de Giessen, David M. Cash, Ruben Smith, Azadeh Feizpour, Ronald Carl Petersen, Niklas Mattsson, Jonathan M. Schott, Bernard Hanseeuw, Nesrine Rahmouni, Fang Xie, Matthias Brendel, Johannes Gnörich, Anouk den Braber, Geidy E. Serrano, Giovanni Battista Frisoni, Gil D. Rabinovici, Konstantin Messerschmidt, Yasmine Salman, William Coath, Victor L. Villemagne, Ingmar Gr. Skoog, William J. Jagust, Yihui Guan, Ian Kennedy, Michael J. Pontecorvo, Suzanne L. Baker, Débora Elisa Peretti, Elena Jaeger, Rik R. Vandenberghe, Michael Schöll, Elizabeth C. Mormino, Alexander Drzezga, Theresa M. Harrison, Silke Kern, Willemijn J. Jansen, Nicolai Franzmeier, Vincent Malotaux, Koen Van Laere, Sylvia Villeneuve, Christina B. Young, Sterling C. Johnson, Carolina Minguillón, Bradford C. Dickerson, Keith A. Johnson, Pedro Rosa‐Neto, Hillary Vossler, Thomas G. Beach, Bradley T. Christian, Mahnaz Shekari, Yolande A.L. Pijnenburg, Jennifer J. Manly, William Charles Kreisl, Liana G. Apostolova, Sang Won Seo, Laure Spruyt, Juan Domingo-Gispert
article en
22 citations

Abstract

Tau positron emission tomography (PET) imaging allows in vivo detection of tau proteinopathy in Alzheimer's disease, which is associated with neurodegeneration and cognitive decline. Understanding how demographic, clinical and genetic factors relate to tau PET positivity will facilitate its use for clinical practice and research. Here we conducted an analysis of 42 cohorts worldwide (N = 12,048), including 7,394 cognitively unimpaired (CU) participants, 2,177 participants with mild cognitive impairment (MCI) and 2,477 participants with dementia. We found that from age 60 years to 80 years, tau PET positivity in a temporal composite region increased from 1.1% to 4.4% among CU amyloid-β (Aβ)-negative participants and from 17.4% to 22.2% among CU Aβ-positive participants. Across the same age span, tau PET positivity decreased from 68.0% to 52.9% in participants with MCI and from 91.5% to 74.6% in participants with dementia. Age, Aβ status, APOE ε4 carriership and female sex were all associated with a higher prevalence of tau PET positivity across groups. APOE ε4 carriership in CU individuals lowered the age at onset of both Aβ positivity and tau positivity by decades. Finally, we replicated these associations in an independent autopsy dataset (N = 5,072 from 3 cohorts).

Nature NeuroscienceVol. 28(8)
University of Geneva (CH), Alzheimer's Association (US), Brigham and Women's Hospital (US), Rush University Medical Center (US), Commonwealth Scientific and Industrial Research Organisation (AU), Centre National de la Recherche Scientifique (FR), Allen Institute for Brain Science (US), Cliniques Universitaires Saint-Luc (BE), University of Wisconsin–Madison (US), Harvard University (US), Lawrence Berkeley National Laboratory (US), Inserm (FR), The University of Melbourne (AU), Eli Lilly (United States) (US), University of Pittsburgh (US), University of California, San Francisco (US), Malmö University (SE), Lund University (SE), MRC Cognition and Brain Sciences Unit (GB), Washington University in St. Louis (US), University of Cambridge (GB), Florey Institute of Neuroscience and Mental Health (AU), Fudan University (CN), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Douglas Mental Health University Institute (CA), Columbia University Irving Medical Center (US), Sahlgrenska University Hospital (SE), German Center for Neurodegenerative Diseases (DE), Samsung Medical Center (KR), Cambridge University Hospitals NHS Foundation Trust (GB), LMU Klinikum (DE), Maastricht University (NL), Gordon Center for Medical Imaging (US), Massachusetts General Hospital (US), Institut d'Imagerie Biomédicale (FR), Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES), University Memory and Aging Center (US), University Hospital of Geneva (CH), Centre Hospitalier d'Orsay (FR), Pasqual Maragall Foundation (ES), Amsterdam Neuroscience (NL), Munich Cluster for Systems Neurology (DE), Mayo Clinic in Arizona (US), University Hospital Leipzig (DE), UK Dementia Research Institute (GB), Athinoula A. Martinos Center for Biomedical Imaging (US), Barcelonaβeta Brain Research Center (ES), CEA Paris-Saclay (FR), Max Planck Institute for Human Cognitive and Brain Sciences (DE), Centre d'Imagerie BioMedicale (CH), Skåne University Hospital (SE), Australian e-Health Research Centre (AU), Cognitive Neuroimaging Lab (FR), Banner Sun Health Research Institute (US), National Hospital for Neurology and Neurosurgery (GB), Amsterdam University Medical Centers (NL), University Hospital Cologne (DE), VIB-KU Leuven Center for Brain & Disease Research (BE), Huashan Hospital (CN), Austin Health (AU), GHU Paris psychiatrie & neurosciences, Indiana University School of Medicine, University College London (GB), Mass General Brigham (US), McGill University (CA), Indiana University – Purdue University Indianapolis (US), Columbia University (US), Ludwig-Maximilians-Universität München (DE), Sungkyunkwan University (KR), Vrije Universiteit Amsterdam (NL), University of Gothenburg (SE), Medical Research Council (GB), University of California, Berkeley (US), Stanford University (US), KU Leuven (BE)
U.S. Department of Defense, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Biogen, University of Southern California, F. Hoffmann-La Roche, Meso Scale Diagnostics, Arizona Department of Health Services, Alzheimer's Disease Neuroimaging Initiative, Cure Alzheimer's Fund, BioClinica, Novartis Pharmaceuticals Corporation, McGill University, Fondation Brain Canada, Northern California Institute for Research and Education, Merck KGaA, Prothena, Australian Government, GHR Foundation, Cerveau Technologies, Government of Canada, Alzheimer Society, European Commission, Commonwealth Scientific and Industrial Research Organisation, ZonMw, Lunds Universitet, Eisai, Knut och Alice Wallenbergs Stiftelse, Novo Nordisk, Vetenskapsrådet, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Alzheimerfonden, Stichting Dioraphte, Alzheimer Nederland, Skånes universitetssjukhus, Servier, H. Lundbeck A/S, IXICO, Fondation pour la Recherche sur Alzheimer, Arizona Biomedical Research Commission, National Institutes of Health, Genentech, EMD Serono, Parkinsonfonden, Pfizer Canada, Avid Radiopharmaceuticals, Irving Medical Center, Columbia University, Canadian Institutes of Health Research, National Health and Medical Research Council, Institut de Recherches Servier, National Institute on Aging
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