Progress regarding the context-of-use of tau as biomarker of Alzheimer’s disease and other neurodegenerative diseases

ABSTRACT

Introduction: Tau protein misfolding and accumulation in toxic species is a critical pathophysiological process of Alzheimer’s disease (AD) and other neurodegenerative disorders (NDDs). Tau biomarkers, namely cerebrospinal fluid (CSF) total-tau (t-tau), 181-phosphorylated tau (p-tau), and tau-PET tracers, have been recently embedded in the diagnostic criteria for AD. Nevertheless, the role of tau as a diagnostic and prognostic biomarker for other NDDs remains controversial.

Areas covered: We performed a systematical PubMed-based review of the most recent advances in tau-related biomarkers for NDDs. We focused on papers published from 2015 to 2020 assessing the diagnostic or prognostic value of each biomarker.

Expert opinion: The assessment of tau biomarkers in alternative easily accessible matrices, through the development of ultrasensitive techniques, represents the most significant perspective for AD-biomarker research. In NDDs, novel tau isoforms (e.g. p-tau217) or proteolytic fragments (e.g. N-terminal fragments) may represent candidate diagnostic and prognostic biomarkers and may help monitoring disease progression. Protein misfolding amplification assays, allowing the identification of different tau strains (e.g. 3 R- vs. 4 R-tau) in CSF, may constitute a breakthrough for the in vivo stratification of NDDs. Tau-PET may help tracking the spatial-temporal evolution of tau pathophysiology in AD but its application outside the AD-spectrum deserves further studies.

KEYWORDS:

• Alzheimer’s disease
• fluid biomarkers
• neurodegenerative diseases
• tau
• tau-PET
• ultrasensitive techniques

Article highlights

• Tau protein misfolding and accumulation in toxic species and tangles is a critical pathophysiological process of Alzheimer’s disease (AD) and other neurodegenerative disorders (NDDs);

• Cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) are included in the current diagnostic criteria for AD; in primary tauopathies and in other NDDs (ALS-FTD spectrum and α-synucleinopathies) the role of tau as a diagnostic and prognostic biomarker is still controversial;

• The quantification of t-tau and p-tau and of emerging tau biomarkers in plasma by using ultrasensitive techniques are gaining momentum in the AD diagnostic workup;

• Novel tau fragments and tau isoforms detectable by means of ultrasensitive methods including Protein Misfolding Cyclic Amplification (PMCA) and Real-time quaking-induced conversion (RT-QuIC) may improve the in vivo stratification of NDDs;

• Tau-PET tracers are useful tools for the in vivo tracking of the spatial-temporal evolution of tau pathophysiology in AD but further studies are needed to define their proper context-of-use in other tauopathies.

Declaration of interest

A. Vergallo and H. Hampel are employees of Eisai Inc. This work has been performed during their previous position at Sorbonne University, Paris, France.

AV does not receive any fees or honoraria since November 2019. Before November 2019 he had he received lecture honoraria from Roche, MagQu LLC, and Servier.

While at Sorbonne University H. Hampel was supported by the AXA Research Fund, the ‘Fondation partenariale Sorbonne Université’ and the ‘Fondation pour la Recherche sur Alzheimer’, Paris, France.

H. Hampel serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019; before May 2019 H. Hampel received lecture fees from Servier, Biogen and Roche; research grants from Pfizer, Avid, and MSD Avenir (paid to the institution); travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE Healthcare and Oryzon Genomics; consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics.

H. Hampel is co-inventor in the following patents as a scientific expert and has received no royalties:

• In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388

• In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784

• Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300

• In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463

• In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286

• In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822

• In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553

• CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797

• In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966

• Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921.

F. Baldacci has received funding from Allergan, Biogen, Eisai, Novartis and travel grants from Allergan, Eli Lilly, Novartis, Teva.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.