Plasma tau levels in Alzheimer's disease
© BioMed Central Ltd 2013
Published: 28 March 2013
Efforts to find reliable blood biomarkers for Alzheimer's disease (AD) in a highly warranted clinical laboratory test have met with little success. There is no clear change in plasma β-amyloid in AD, and assays for the axonal injury marker tau have been hampered by a lack of analytical sensitivity for accurate measurement in blood samples . Here, the results of a novel ultra-sensitive assay for tau in peripheral blood are reported.
We have developed an ultra-sensitive assay for tau in peripheral blood . In brief, the assay is based on digital array technology  and uses the Tau5 monoclonal antibody for capture (Covance, Princeton, NJ, USA) and HT7 and BT2 monoclonal antibodies for detection (Pierce, now part of Thermo Fisher Scientific Inc., Waltham, MA, USA). This combination reacts with both normal and phosphorylated tau with epitopes in the mid-region of the molecule, making the assay sensitive to all known tau isoforms. The calibrator was recombinant tau 381 (EMD Millipore Corporation, Billerica, MA, USA). To minimize matrix effects, all samples were diluted 1:4 in phosphate-buffered saline with 2% bovine serum albumin diluent prior to assay. The limit of detection of the assay, which requires 30 μL of plasma, is 0.02 pg/mL , which is more than 1,000-fold more sensitive than conventional immunoassays.
Demographic and biochemical data
AD (n= 54)
MCI (n= 75)
Controls (n= 25)
Plasma T-tau, pg/mL
CSF T-tau, pg/mL
CSF P-tau, pg/mL
CSF Aβ42, pg/mL
The results of this study have several important implications. First, plasma tau levels are elevated in AD but with overlapping ranges across diagnostic groups. This overlap diminishes the utility of plasma tau as a diagnostic test. However, further studies are needed to evaluate plasma tau as a first-in-line screening tool (for example, in the primary care setting and perhaps together with other markers in a biomarker panel). Second, normal plasma tau levels in the MCI stage of AD suggest that plasma tau is a late marker, requiring substantial axonal injury before increasing to abnormal levels. In this context, other neurodegenerative diseases (for example, Creutzfeldt-Jakob disease) as well as acute conditions (for example, stroke and brain trauma) should be tested. Third, the lack of correlation of tau levels in plasma and CSF suggests that steady-state concentrations of tau in these two body fluids are differentially regulated. In our earlier study of patients with hypoxic brain injury following cardiac arrest, tau was rapidly (within 24 hours) cleared from blood in patients with good neurological outcome , indicating potent clearance mechanisms for this marker in the bloodstream. This may obscure any correlation with CSF tau levels, which stay elevated for weeks following an acute neurological insult .
This article is part of a series on Peripheral Biomarkers, edited by Douglas Galasko. Other articles in this series can be found at http://alzres.com/series/biomarkers
mild cognitive impairment.
This study was funded by grants from Swedish Brain Power, the Swedish Research Council, the Wolfson Foundation, the Alzheimer's Association, the JPND Project BIOMARKAPD, Swedish State Support for Clinical Research, the Swedish Brain Fund, the Alzheimer Foundation of Sweden, and the Dementia Association of Sweden.
- Blennow K, Hampel H, Weiner M, Zetterberg H: Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010, 6: 131-144. 10.1038/nrneurol.2010.4.View ArticlePubMedGoogle Scholar
- Randall J, Mörtberg E, Provuncher GK, Fournier DR, Duffy DC, Rubertsson S, Blennow K, Zetterberg H, Wilson DH: Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: results of a pilot study. Resuscitation. 2012, Aug 9,Google Scholar
- Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Piech T, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walt DR, Duffy DC: Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol. 2010, 28: 595-599. 10.1038/nbt.1641.PubMed CentralView ArticlePubMedGoogle Scholar
- McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984, 34: 939-944. 10.1212/WNL.34.7.939.View ArticlePubMedGoogle Scholar
- Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC: Mild cognitive impairment - beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004, 256: 240-246. 10.1111/j.1365-2796.2004.01380.x.View ArticlePubMedGoogle Scholar
- Hesse C, Rosengren L, Andreasen N, Davidsson P, Vanderstichele H, Vanmechelen E, Blennow K: Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett. 2001, 297: 187-190. 10.1016/S0304-3940(00)01697-9.View ArticlePubMedGoogle Scholar