Review

. 2021 Jul;48(7):2140-2156.

doi: 10.1007/s00259-021-05253-y. Epub 2021 Mar 6.

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

N J Ashton^{1

2

3}, A Leuzy⁴, T K Karikari⁵, N Mattsson-Carlgren^{4

6

7}, A Dodich^{8

9}, M Boccardi^{10

11}, J Corre¹², A Drzezga¹³, A Nordberg^{14

15}, R Ossenkoppele^{4

16}, H Zetterberg^{5

17

18

19}, K Blennow^{5

17}, G B Frisoni^{10

20}, V Garibotto^{8

21}, O Hansson^{22

23

24}

Affiliations

¹ Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, Sahlgrenska Academy, University of Gothenburg, House V3/SU, SE-431 80, Mölndal, Sweden. nicholas.ashton@gu.se.
² Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. nicholas.ashton@gu.se.
³ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. nicholas.ashton@gu.se.
⁴ Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
⁵ Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, Sahlgrenska Academy, University of Gothenburg, House V3/SU, SE-431 80, Mölndal, Sweden.
⁶ Department of Neurology, Skåne University Hospital, Lund, Sweden.
⁷ Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
⁸ NIMTlab - Neuroimaging and Innovative Molecular Tracers Laboratory, University of Geneva, Geneva, Switzerland.
⁹ Center for Neurocognitive Rehabilitation (CeRiN), CIMeC, University of Trento, Trento, Italy.
¹⁰ German Center for Neurodegenerative Diseases (DZNE), Rostock-Greifswald, Rostock, Germany.
¹¹ LANVIE - Laboratory of Neuroimaging of Aging, University of Geneva, Geneva, Switzerland.
¹² Centre National de la Recherche Scientifique, Montpellier, France.
¹³ Medical Faculty and University Hospital of Cologne, Cologne, Germany.
¹⁴ Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Theme Aging, Karolinska University Hospital Stockholm, Stockholm, Sweden.
¹⁶ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
¹⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁸ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁹ UK Dementia Research Institute at UCL, London, UK.
²⁰ Memory Clinic, Geneva University Hospitals, Geneva, Switzerland.
²¹ Diagnostic Department, University Hospitals of Geneva, Geneva, Switzerland.
²² Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden. Oskar.Hansson@med.lu.se.
²³ UK Dementia Research Institute at UCL, London, UK. Oskar.Hansson@med.lu.se.
²⁴ Memory Clinic, Skåne University Hospital, SE-205 02, Malmö, Sweden. Oskar.Hansson@med.lu.se.

PMID: 33677733
PMCID: PMC8175325
DOI: 10.1007/s00259-021-05253-y

Review

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

N J Ashton et al. Eur J Nucl Med Mol Imaging. 2021 Jul.

. 2021 Jul;48(7):2140-2156.

doi: 10.1007/s00259-021-05253-y. Epub 2021 Mar 6.

Authors

Affiliations

¹ Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, Sahlgrenska Academy, University of Gothenburg, House V3/SU, SE-431 80, Mölndal, Sweden. nicholas.ashton@gu.se.
² Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. nicholas.ashton@gu.se.
³ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. nicholas.ashton@gu.se.
⁴ Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
⁵ Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, Sahlgrenska Academy, University of Gothenburg, House V3/SU, SE-431 80, Mölndal, Sweden.
⁶ Department of Neurology, Skåne University Hospital, Lund, Sweden.
⁷ Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
⁸ NIMTlab - Neuroimaging and Innovative Molecular Tracers Laboratory, University of Geneva, Geneva, Switzerland.
⁹ Center for Neurocognitive Rehabilitation (CeRiN), CIMeC, University of Trento, Trento, Italy.
¹⁰ German Center for Neurodegenerative Diseases (DZNE), Rostock-Greifswald, Rostock, Germany.
¹¹ LANVIE - Laboratory of Neuroimaging of Aging, University of Geneva, Geneva, Switzerland.
¹² Centre National de la Recherche Scientifique, Montpellier, France.
¹³ Medical Faculty and University Hospital of Cologne, Cologne, Germany.
¹⁴ Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Theme Aging, Karolinska University Hospital Stockholm, Stockholm, Sweden.
¹⁶ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
¹⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁸ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁹ UK Dementia Research Institute at UCL, London, UK.
²⁰ Memory Clinic, Geneva University Hospitals, Geneva, Switzerland.
²¹ Diagnostic Department, University Hospitals of Geneva, Geneva, Switzerland.
²² Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden. Oskar.Hansson@med.lu.se.
²³ UK Dementia Research Institute at UCL, London, UK. Oskar.Hansson@med.lu.se.
²⁴ Memory Clinic, Skåne University Hospital, SE-205 02, Malmö, Sweden. Oskar.Hansson@med.lu.se.

PMID: 33677733
PMCID: PMC8175325
DOI: 10.1007/s00259-021-05253-y

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.

Keywords: Alzheimer’s disease; Aβ40; Aβ42; Blood; P-tau; Strategic roadmap.

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Conflict of interest statement

HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau and Roche. VG received financial support for research through her institution from Siemens Healthineers, GE Healthcare, Life Molecular Imaging, Cerveau Technologies, Roche, Merck and consultancy/speaker fees from Siemens Healthineers and GE Healthcare. NJA, AL, TKK, NMC, AD, MB, CJ and GBF report no conflicts of interest.

Figures

**Fig. 1**
A flowchart illustrating the development of blood biomarkers, p-tau (a) and Aβ (b) for AD in the framework of Pepe et al. (2001). Abbreviations: AD, Alzheimer’s disease; HC, healthy controls; *MCI*, mild cognitive impairment

See this image and copyright information in PMC

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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LinkOut - more resources

Full Text Sources

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Medical