Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer's disease

The tau protein plays a central role in Alzheimer's disease (AD), and there is huge interest in measuring tau in blood and cerebrospinal fluid (CSF). We developed a set of immunoassays to measure tau in specimens from humans diagnosed based on current best clinical and CSF biomarker criteria. I...

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Published in	Alzheimer's & dementia Vol. 15; no. 3; pp. 487 - 496
Main Authors	Chen, Zhicheng, Mengel, David, Keshavan, Ashvini, Rissman, Robert A., Billinton, Andrew, Perkinton, Michael, Percival-Alwyn, Jennifer, Schultz, Aaron, Properzi, Michael, Johnson, Keith, Selkoe, Dennis J., Sperling, Reisa A., Patel, Purvish, Zetterberg, Henrik, Galasko, Douglas, Schott, Jonathan M., Walsh, Dominic M.
Format	Journal Article
Language	English
Published	United States Elsevier Inc 01.03.2019
Subjects	Aged Alzheimer Disease - blood Alzheimer Disease - cerebrospinal fluid association big-tau Biomarker biomarkers Biomarkers - blood Biomarkers - cerebrospinal fluid cerebrospinal-fluid tau Cognitive Dysfunction - blood Cognitive Dysfunction - cerebrospinal fluid Cohort Studies csf Dementia diagnosis Diagnosis, Differential Enzyme-linked immunoassay Extracellular Space Female Humans Immunoassay - methods Male Middle Aged Mild cognitive impairment Neurosciences Neurovetenskaper Plasma plasma tau protein Sensitivity and Specificity Single Single molecule array tau Proteins - blood tau Proteins - cerebrospinal fluid Plasma Biomarker Enzyme-linked immunoassay Mild cognitive impairment Dementia Single molecule array
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ISSN	1552-5260 1552-5279 1552-5279
DOI	10.1016/j.jalz.2018.09.010

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Summary:	The tau protein plays a central role in Alzheimer's disease (AD), and there is huge interest in measuring tau in blood and cerebrospinal fluid (CSF). We developed a set of immunoassays to measure tau in specimens from humans diagnosed based on current best clinical and CSF biomarker criteria. In CSF, mid-region- and N-terminal-detected tau predominated and rose in disease. In plasma, an N-terminal assay (NT1) detected elevated levels of tau in AD and AD-mild cognitive impairment (MCI). Plasma NT1 measurements separated controls from AD-MCI (area under the curve [AUC] = 0.88) and AD (AUC = 0.96) in a discovery cohort and in a Validation Cohort (with AUCs = 0.79 and 0.75, respectively). The forms of tau in CSF and plasma are distinct, but in each specimen type, the levels of certain fragments are increased in AD. Measurement of plasma NT1 tau should be aggressively pursued as a potential blood-based screening test for AD/AD-MCI.
Bibliography:	These authors contributed equally. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 DMW conceived the project, designed and supervised the research and wrote the manuscript. ZC developed all novel tau assays described herein and analyzed samples. AK collected certain clinical samples and performed analyses using the INNOTEST kits. DM helped validate novel tau assays, analyzed certain samples, prepared the Figures and conducted statistical comparisons. RR and DG supplied archived samples and relevant clinical data. AB, AP and JPA made and supplied antibody TauAB. AS, MP, KJ, DJS and RS contributed samples and relevant clinical data. PP provided expert assistance for the development of Simoa-based assays. JS and HZ supervised collection of the UCL cohort and analysis of CSF specimens using INNOTEST ELISAs. All the authors critically assessed and contributed to writing the manuscript. Author contributions
ISSN:	1552-5260 1552-5279 1552-5279
DOI:	10.1016/j.jalz.2018.09.010