{"id":"doi:10.1007/s00401-021-02275-6","kind":"article","title":"Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology","authors":["Ashton NJ","Pascoal TA","Karikari TK","Benedet AL","Lantero-Rodriguez J","Brinkmalm G","Snellman A","Schöll M","Troakes C","Hye A","Gauthier S","Vanmechelen E","Zetterberg H","Rosa-Neto P","Blennow K"],"author_count":15,"year":2021,"published":"2021-02-14","venue":"Acta neuropathologica","cited_by":615,"doi":"10.1007/s00401-021-02275-6","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1007/s00401-021-02275-6","archive_url":"https://space-kitty.com/papers/doi:10.1007/s00401-021-02275-6","updated":null,"pmid":"33585983","pmcid":"PMC8043944","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC8043944/pdf","abstract":"The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer's disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92-0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [ 18 F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [ 18 F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [ 18 F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2-4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3-4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I-II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology\" by Ashton NJ, Pascoal TA, Karikari TK et al., https://doi.org/10.1007/s00401-021-02275-6, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"neurodegeneration","name":"Alzheimer's, Parkinson's & Neurodegeneration","domain_slug":"medicine"}],"cited_in_dossiers":[]}