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

Zhicheng Chen; David Mengel; Ashvini Keshavan; Robert A Rissman; Andrew Billinton; Michael Perkinton; Jennifer Percival-Alwyn; Aaron Schultz; Michael Properzi; Keith Johnson; Dennis J Selkoe; Reisa A Sperling; Purvish Patel; Henrik Zetterberg; Douglas Galasko; Jonathan M Schott; Dominic M Walsh

doi:10.1016/j.jalz.2018.09.010

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

Alzheimers Dement. 2019 Mar;15(3):487-496. doi: 10.1016/j.jalz.2018.09.010. Epub 2018 Nov 9.

Authors

Zhicheng Chen¹, David Mengel¹, Ashvini Keshavan², Robert A Rissman³, Andrew Billinton⁴, Michael Perkinton⁴, Jennifer Percival-Alwyn⁴, Aaron Schultz⁵, Michael Properzi⁵, Keith Johnson⁵, Dennis J Selkoe¹, Reisa A Sperling¹, Purvish Patel⁶, Henrik Zetterberg⁷, Douglas Galasko⁸, Jonathan M Schott², Dominic M Walsh⁹

Affiliations

¹ Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England.
³ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA.
⁴ AstraZeneca Neuroscience Innovative Medicines, MedImmune Ltd, Cambridge, England.
⁵ Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
⁶ Quanterix Corporation, Lexington, MA, USA.
⁷ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England; UK Dementia Research Institute at UCL, London, England; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁸ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
⁹ Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, England. Electronic address: dwalsh3@bwh.harvard.edu.

Abstract

Introduction: 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).

Methods: We developed a set of immunoassays to measure tau in specimens from humans diagnosed based on current best clinical and CSF biomarker criteria.

Results: 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).

Discussion: 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.

Keywords: Biomarker; Dementia; Enzyme-linked immunoassay; Mild cognitive impairment; Plasma; Single molecule array.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Validation Study

MeSH terms

Aged
Alzheimer Disease / blood*
Alzheimer Disease / cerebrospinal fluid
Biomarkers / blood
Biomarkers / cerebrospinal fluid
Cognitive Dysfunction / blood*
Cognitive Dysfunction / cerebrospinal fluid
Cohort Studies
Diagnosis, Differential
Extracellular Space
Female
Humans
Immunoassay* / methods
Male
Middle Aged
Sensitivity and Specificity
tau Proteins / blood*
tau Proteins / cerebrospinal fluid

Substances

Biomarkers
MAPT protein, human
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding