Plasma p-tau181 accurately predicts Alzheimer's disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline

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• dc.contributor.author Lantero Rodriguez, Juan
• dc.contributor.author Karikari, Thomas K.
• dc.contributor.author Suárez-Calvet, Marc
• dc.contributor.author Troakes, Claire
• dc.contributor.author King, Andrew
• dc.contributor.author Emersic, Andreja
• dc.contributor.author Aarsland, Dag
• dc.contributor.author Hye, Abdul
• dc.contributor.author Zetterberg, Henrik
• dc.contributor.author Blennow, Kaj
• dc.contributor.author Ashton, Nicholas J.
• dc.date.accessioned 2020-09-04T06:43:48Z
• dc.date.available 2020-09-04T06:43:48Z
• dc.date.issued 2020
• dc.description.abstract The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer's disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2 years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8 years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC = 97.4%, 95% CI = 94.1-100%) even 8 years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4 years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials.
• dc.description.sponsorship Open access funding provided by University of Gothenburg. This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Tissue samples were supplied by The London Neurodegenerative Diseases Brain Bank, which receives funding from the UK Medical Research Council and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. TKK holds a postdoctoral fellowship from the BrightFocus Foundation (#A2020812F), and was further supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Agneta Prytz-Folkes and Gösta Folkes Foundation, Gamla Tjänarinnor, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. MSC received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement no. 752310, and currently receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). AH is funded by Research Centre for Mental Health and Biomedical Research Unit for Dementia. KB holds the Torsten Söderberg Professorship in Medicine and is supported by grants from the Swedish Research Council, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. AH is funded by Research Centre for Mental Health and Biomedical Research Unit for Dementia. KB holds the Torsten Söderberg Professorship in Medicine and is supported by grants from the Swedish Research Council, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences, and is supported by the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), and a grant (#ALFGBG-715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement. NJA is supported by the Wallenberg Centre for Molecular and Translational Medicine, the Swedish Alzheimer Foundation (Alzheimerfonden), the Swedish Dementia Foundation (Demensförbundet), and Hjärnfonden, Sweden.
• dc.format.mimetype application/pdf
• dc.identifier.citation Lantero Rodriguez J, Karikari TK, Suárez-Calvet M, Troakes C, King A, Emersic A. et al. Plasma p-tau181 accurately predicts Alzheimer's disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline. Acta Neuropathol. 2020 Sep; 140(3):267-278. DOI: 10.1007/s00401-020-02195-x
• dc.identifier.doi http://dx.doi.org/10.1007/s00401-020-02195-x
• dc.identifier.issn 0001-6322
• dc.identifier.uri http://hdl.handle.net/10230/45253
• dc.language.iso eng
• dc.publisher SpringerOpen
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/752310
• dc.rights This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Alzheimer’s disease
• dc.subject.keyword Blood biomarkers
• dc.subject.keyword Braak
• dc.subject.keyword Neuropathology
• dc.subject.keyword p-tau181
• dc.title Plasma p-tau181 accurately predicts Alzheimer's disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion