Journal
ACTA NEUROPATHOLOGICA
Volume 140, Issue 3, Pages 267-278Publisher
SPRINGER
DOI: 10.1007/s00401-020-02195-x
Keywords
Alzheimer's disease; Neuropathology; Braak; Blood biomarkers; p-tau181
Categories
Funding
- University of Gothenburg
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London
- UK Medical Research Council
- Alzheimer's Research UK
- Alzheimer's Society
- BrightFocus Foundation [A2020812F]
- Swedish Alzheimer Foundation (Alzheimerfonden) [AF-930627]
- Swedish Brain Foundation (Hjarnfonden) [FO2020-0240]
- Swedish Dementia Foundation (Demensforbundet)
- Agneta Prytz-Folkes and Gosta Folkes Foundation
- Gamla Tjanarinnor
- Gun and Bertil Stohnes Foundation
- Anna Lisa and Brother Bjornsson's Foundation
- European Union [752310]
- Instituto de Salud Carlos III [PI19/00155]
- Spanish Ministry of Science, Innovation and Universities [IJC2018-037478-I]
- Research Centre for Mental Health and Biomedical Research Unit for Dementia
- Swedish Research Council
- Swedish Alzheimer Foundation
- Swedish Brain Foundation
- Swedish Research Council [2017-00915]
- Swedish Alzheimer Foundation [AF-742881]
- Hjarnfonden, Sweden [FO2017-0243]
- Swedish government [ALFGBG-715986]
- Wallenberg Centre for Molecular and Translational Medicine
- Swedish Alzheimer Foundation (Alzheimerfonden)
- Hjarnfonden, Sweden
- Aina (Ann) Wallstroms and Mary-Ann Sjobloms Foundation
- Marie Curie Actions (MSCA) [752310] Funding Source: Marie Curie Actions (MSCA)
- MRC [UKDRI-1003, MR/L016397/1] Funding Source: UKRI
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The neuropathological confirmation of amyloid-beta (A beta) 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.
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