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The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

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Ashton, N. J., Leuzy, A., Karikari, T. K., Mattsson-Carlgren, N., Dodich, A., Boccardi, M., Corre, J., Drzezga, A. +7 more·2021·European Journal of Nuclear Medicine and Molecular Imaging
DOI 10.1007/s00259-021-05253-yPMC PMC8175325
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Abstract

Purpose: The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers. Methods: A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Results: Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aβ remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aβ, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria. Conclusions: Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 – with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.

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  • Blood tests to measure Aβ peptides, total and phospho-tau have the potential for screening asymptomatic individuals and aiding diagnosis of symptomatic patients.

    “Blood test to measure Aβ peptides, total and phospho-tau are much more appropriate tools, and regardless of their own and significant challenges, they have the potential for screening asymptomatic individuals and to aid in diagnosing symptomatic patients (Ashton et al., 2021).”

    From Small nucleolar RNAs in plasma extracellular vesicles and their discriminatory power as diagnostic biomarkers of Alzheimer's disease (2021) · cites this paper as Ashton et al., 2021

    The Discussion (page not supplied) says plasma p-tau could aid diagnosis in patients with dementia and that plasma Aβ may help predict preclinical AD. But the Results, Phase 1 (page not supplied), explicitly says blood total tau is not diagnostically useful for AD, so the claim overextends that potential to total tau. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • The diagnostic power of the biomarkers varied in different studies.

    “The diagnostic power of the biomarkers also varied in different studies49,50.”

    From Integrated algorithm combining plasma biomarkers and cognitive assessments accurately predicts brain β-amyloid pathology (2023) · cites this paper as [50]

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Authors
Ashton, N. J., Leuzy, A., Karikari, T. K., Mattsson-Carlgren, N., Dodich, A., Boccardi, M., Corre, J., Drzezga, A., Nordberg, A., Ossenkoppele, R., Zetterberg, H., Blennow, K., Frisoni, G. B., Garibotto, V., & Hansson, O.
Affiliations
  • King's College London (GB)
  • Lund University (SE)
  • University of Gothenburg (SE)
  • University of Geneva (CH)
  • Centre National de la Recherche Scientifique (FR)
  • University of Cologne (DE)
  • Karolinska University Hospital (SE)
  • Sahlgrenska University Hospital (SE)
  • German Center for Neurodegenerative Diseases (DE)
Corresponding author
  • Ashton, N. J.
  • Hansson, O.
ORCID
Venue
European Journal of Nuclear Medicine and Molecular Imaging
Publisher
Springer Science and Business Media LLC
Published
2021-03-06
Volume
48
Issue
7
Pages
2140-2156
ISSN
  • 1619-7070 (ISSN-L)
  • 1619-7089
DOI
10.1007/s00259-021-05253-y
PMC
PMC8175325
OpenAlex
W3135004658
Cited by
142
References
135
Citations by year
2026: 12 · 2025: 13 · 2024: 26 · 2023: 24 · 2022: 44 · 2021: 23
FWCI
5.22
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Nuclear Medicine and Molecular Imaging (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
  • Institutional Research Information System (Università degli Studi di Trento) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • DZNE Pub (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
University of Gothenburg
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
Keywords
Alzheimer's disease, blood biomarkers, phosphorylated tau, amyloid-beta, biomarker validation, differential diagnosis of dementia, early detection, cerebrospinal fluid biomarkers, PET biomarkers, disease progression prediction
MeSH terms
Alzheimer Disease, Humans, Peptide Fragments, Tomography, X-Ray Computed, Biomarkers, Amyloid beta-Peptides, tau Proteins

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