Association of Phosphorylated Tau Biomarkers with Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

Joseph Therriault, Marie Vermeiren, Stijn Servaes, Cécile Tissot, Nicholas J. Ashton, Andréa Lessa Benedet, Thomas K. Karikari, Juan Lantero-Rodriguez, Wagner S. Brum, Firoza Z. Lussier, Gleb Bezgin, Jenna Stevenson, Nesrine Rahmouni, Peter Kunach, Yi Ting Wang, Jaime Fernandez-Arias, Kely Quispialaya Socualaya, Arthur C. Macedo, João Pedro Ferrari-Souza, Pâmela C.L. FerreiraBruna Bellaver, Douglas T. Leffa, Eduardo R. Zimmer, Paolo Vitali, Jean Paul Soucy, Gallen Triana-Baltzer, Hartmuth C. Kolb, Tharick A. Pascoal, Paramita Saha-Chaudhuri, Serge Gauthier, Henrik Zetterberg, Kaj Blennow, Pedro Rosa-Neto*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Importance: The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles. Objective: To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET). Design, Setting, and Participants: This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded. Exposures: Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay. Main Outcomes and Measures: Associations between p-tau biomarkers with amyloid PET and tau PET. Results: A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181difference, 13%; 95% CI, 3%-22%; P =.006; p-tau217difference, 11%; 95% CI, 3%-20%; P =.003; p-tau231difference, 15%; 95% CI, 5%-22%; P <.001; p-tau235difference, 9%; 95% CI, 1%-19%; P =.02). These results were replicated with plasma p-tau181(difference, 11%; 95% CI, 1%-22%; P =.02), p-tau217(difference, 9%; 95% CI, 1%-19%; P =.02), p-tau231(difference, 13%; 95% CI, 3%-24%; P =.009), and CSF p-tau181(difference, 9%; 95% CI, 1%-21%; P =.02) in independent cohorts. Conclusions and Relevance: Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Original languageEnglish
Pages (from-to)188-199
Number of pages12
JournalJAMA Neurology
Volume80
Issue number2
DOIs
Publication statusPublished - Feb 2023

Bibliographical note

Funding/Support: This work was supported by grants MOP-11-51-31 and RFN 152985, 159815, 162303 from the Canadian Institutes of Health Research (CIHR); MOP-11-51-31 from the Canadian Consortium of Neurodegeneration and Aging (CCNA); the Weston Brain Institute; grants NIRG-12-92090, NIRP-12-259245 from the Alzheimer’s Association; grants 34874 and 33397 from Brain Canada Foundation; 2020-VICO-279314 from the Fonds de Recherche du Québec—Santé (FRQS); the CIHR doctoral award (Dr Therriault); and Alzheimer Nederland (Dr Vermeiren). Dr Karikari was supported by grants 2021-03244 from the Swedish Research Council; AARF-21-850325 from the Alzheimer’s Association; A2020812F from the BrightFocus Foundation; the International Society for Neurochemistry’s Career Development Grant; AF-930627 from the Swedish Alzheimer Foundation; FO2020-0240 from the Swedish Brain Foundation; the Swedish Dementia Foundation; the Swedish Parkinson Foundation; the Gamla Tjänarinnor Foundation; the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation; 2020-00124 from the Agneta Prytz-Folkes & Gösta Folkes Foundation; the Gun and Bertil Stohnes Foundation; and the Anna Lisa and Brother Björnsson’s Foundation. Dr Zetterberg is a Wallenberg Scholar supported by grant 2018-02532 from the Swedish Research Council; 681712 from the European Research Council; ALFGBG-71320 from Swedish State Support for Clinical Research; 201809-2016862 from the Alzheimer Drug Discovery Foundation; ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C from the AD Strategic Fund and the Alzheimer’s Association; the Olav Thon Foundation; the Erling-Persson Family Foundation; FO2019-0228 from Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE); JPND2021-00694 from the European Union Joint Programme—Neurodegenerative Disease Research; and UKDRI-1003 from the UK Dementia Research Institute at UCL. Dr Blennow is supported by grant 2017-00915 from the Swedish Research Council; RDAPB-201809-2016615 from the Alzheimer Drug Discovery Foundation; AF-930351, AF-939721, and AF-968270 from the Swedish Alzheimer Foundation; Hjärnfonden, Sweden; grants FO2017-0243 and ALZ2022-0006 from the Swedish state under the agreement between the Swedish government and the County Councils; ALFGBG-715986 and ALFGBG-965240 from the ALF agreement; JPND2019-466-236 from the European Union Joint Program for Neurodegenerative Disorders; 1R01AG068398-01 from the National Institutes of Health; and ZEN-21-848495 from the Alzheimer’s Association 2021 Zenith Award.

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