Identification of late-stage tau accumulation using plasma phospho-tau217

Marcel S Woo; Joseph Therriault; Erin M Jonaitis; Rachael Wilson; Rebecca E Langhough; Nesrine Rahmouni; Andrea Lessa Benedet; Nicholas J Ashton; Cécile Tissot; Juan Lantero-Rodriguez; Arthur C Macedo; Stijn Servaes; Yi-Ting Wang; Jaime Fernandez Arias; Seyyed Ali Hosseini; Tobey J Betthauser; Firoza Z Lussier; Robert Hopewell; Gallen Triana-Baltzer; Hartmuth C Kolb; Andreas Jeromin; Eliane Kobayashi; Gassan Massarweh; Manuel A Friese; Jesse Klostranec; Paolo Vilali; Tharick A Pascoal; Serge Gauthier; Henrik Zetterberg; Kaj Blennow; Sterling C Johnson; Pedro Rosa-Neto

doi:10.1016/j.ebiom.2024.105413

Identification of late-stage tau accumulation using plasma phospho-tau217

EBioMedicine. 2024 Nov:109:105413. doi: 10.1016/j.ebiom.2024.105413. Epub 2024 Nov 4.

Authors

Marcel S Woo¹, Joseph Therriault², Erin M Jonaitis³, Rachael Wilson⁴, Rebecca E Langhough³, Nesrine Rahmouni⁵, Andrea Lessa Benedet⁶, Nicholas J Ashton⁷, Cécile Tissot⁸, Juan Lantero-Rodriguez⁶, Arthur C Macedo², Stijn Servaes⁵, Yi-Ting Wang², Jaime Fernandez Arias⁵, Seyyed Ali Hosseini⁵, Tobey J Betthauser³, Firoza Z Lussier⁹, Robert Hopewell¹⁰, Gallen Triana-Baltzer¹¹, Hartmuth C Kolb¹¹, Andreas Jeromin¹², Eliane Kobayashi⁶, Gassan Massarweh¹⁰, Manuel A Friese¹³, Jesse Klostranec¹⁴, Paolo Vilali², Tharick A Pascoal⁹, Serge Gauthier², Henrik Zetterberg¹⁵, Kaj Blennow¹⁶, Sterling C Johnson¹⁷, Pedro Rosa-Neto¹⁸

Affiliations

¹ Institute of Neuroimmunology and Multiple Sclerosis, University Medical Centre Hamburg Eppendorf, 20251, Hamburg, Germany; Department of Neurology, University Medical Centre Hamburg Eppendorf, 20251, Hamburg, Germany; Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Montreal, Quebec, QC H4H 1R3, Canada. Electronic address: m.woo@uke.de.
² Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Montreal, Quebec, QC H4H 1R3, Canada; Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, Quebec, QC H3A 1A1, Canada.
³ Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53726, USA.
⁴ Wisconsin Alzheimer's Disease Research Centre, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53726, USA.
⁵ Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Montreal, Quebec, QC H4H 1R3, Canada.
⁶ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
⁷ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 40530, Gothenburg, Sweden.
⁸ Molecular Biophysics and Integrated Bioimaging Department, Lawrence Berkeley National Laboratory, Berkeley, 510, CA, USA.
⁹ Department of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
¹⁰ Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, Quebec, QC H3A 1A1, Canada.
¹¹ Neuroscience Biomarkers, Johnson and Johnson Medical Innovation (formerly Janssen Research & Development), La Jolla, CA, 92121, USA.
¹² ALZpath. Inc, Carlsbad, CA, 92008, USA.
¹³ Institute of Neuroimmunology and Multiple Sclerosis, University Medical Centre Hamburg Eppendorf, 20251, Hamburg, Germany.
¹⁴ Montreal Neurologic Institute and Hospital, Department of Diagnostic and Interventional Neuroradiology, McGill University Health Centre, 3801 Rue University, Montréal, QC, H3A 2B4, Canada.
¹⁵ Wisconsin Alzheimer's Disease Research Centre, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53726, USA; Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1E 6BT, UK; UK Dementia Research Institute at UCL, London, WC1E 6BT, UK; Hong Kong Centre for Neurodegenerative Diseases, Clear Water Bay, 518172 Hong Kong, China.
¹⁶ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden.
¹⁷ Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53726, USA; Wisconsin Alzheimer's Disease Research Centre, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53726, USA.
¹⁸ Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Montreal, Quebec, QC H4H 1R3, Canada; Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, Quebec, QC H3A 1A1, Canada. Electronic address: pedro.rosa@mcgill.ca.

Abstract

Background: Blood-based disease staging across the Alzheimer's disease (AD) continuum holds the promise to identify individuals that profit from disease-modifying therapies. We set out to identify Braak V⁺ (Braak V and/or VI) tau PET-positive individuals within amyloid-β (Aβ)-positive individuals using plasma biomarkers.

Methods: In this cross-sectional study, we assessed 289 individuals from the TRIAD cohort and 306 individuals from the WRAP study across the AD continuum. The participants were evaluated by amyloid-PET with [¹⁸F]AZD4694 or [¹¹C]PiB and tau-PET with [¹⁸F]MK6240 and measured plasma levels included total tau, phospho-tau isoforms (pTau) pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers using different analytic platforms to predict Braak V⁺ positivity in Aβ+ individuals.

Findings: Highest associations with Braak V⁺ tau positivity in Aβ+ individuals were found for plasma pTau-217+^Janssen (AUC [CI_95%] = 0.97 [0.94, 1.0]) and ALZpath pTau-217 (AUC [CI_95%] = 0.93 [0.86, 1.0]) in TRIAD. Plasma ALZpath pTau-217 separated Braak V⁺ tau PET-positive individuals in the WRAP longitudinal study (AUC [CI_95%] = 0.97 [0.94, 1.0]).

Interpretation: Thus, we demonstrate that using adjusted cut-offs, plasma pTau-217 identifies individuals with later Braak stage tau accumulation which will be helpful to stratify patients for treatments and clinical studies.

Funding: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR) [MOP-11-51-31; RFN 152985, 159815, 162303], Canadian Consortium of Neurodegeneration and Aging (CCNA; MOP-11-51-31 -team 1), the Alzheimer's Association [NIRG-12-92090, NIRP-12-259245], Brain Canada Foundation (CFI Project 34874; 33397), the Fonds de Recherche du Québec-Santé (FRQS; Chercheur Boursier, 2020-VICO-279314). P.R-N and SG are members of the CIHR-CCNA Canadian Consortium of Neurodegeneration in Aging. Colin J. Adair Charitable Foundation.

Keywords: Alzheimer's disease; Blood biomarker; Prognosis; p-tau217.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / blood
Alzheimer Disease* / diagnosis
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides / blood
Amyloid beta-Peptides / metabolism
Biomarkers* / blood
Cross-Sectional Studies
Female
Humans
Male
Middle Aged
Phosphorylation
Positron-Emission Tomography*
tau Proteins* / blood
tau Proteins* / metabolism

Substances

tau Proteins
Biomarkers
Amyloid beta-Peptides