Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort

Sarah Westwood; Alison L Baird; Sneha N Anand; Alejo J Nevado-Holgado; Andrey Kormilitzin; Liu Shi; Abdul Hye; Nicholas J Ashton; Angharad R Morgan; Isabelle Bos; Stephanie J B Vos; Susan Baker; Noel J Buckley; Mara Ten Kate; Philip Scheltens; Charlotte E Teunissen; Rik Vandenberghe; Silvy Gabel; Karen Meersmans; Sebastiaan Engelborghs; Ellen E De Roeck; Kristel Sleegers; Giovanni B Frisoni; Olivier Blin; Jill C Richardson; Régis Bordet; José L Molinuevo; Lorena Rami; Anders Wallin; Petronella Kettunen; Magda Tsolaki; Frans Verhey; Alberto Lléo; Isabel Sala; Julius Popp; Gwendoline Peyratout; Pablo Martinez-Lage; Mikel Tainta; Peter Johannsen; Yvonne Freund-Levi; Lutz Frölich; Valerija Dobricic; Cristina Legido-Quigley; Lars Bertram; Frederik Barkhof; Henrik Zetterberg; B Paul Morgan; Johannes Streffer; Pieter Jelle Visser; Simon Lovestone

doi:10.3233/JAD-190434

Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort

Sarah Westwood, Alison L Baird, Sneha N Anand, Alejo J Nevado-Holgado, Andrey Kormilitzin, Liu Shi, Abdul Hye, Nicholas J Ashton, Angharad R Morgan, Isabelle Bos, Stephanie J B Vos, Susan Baker, Noel J Buckley, Mara Ten Kate, Philip Scheltens, Charlotte E Teunissen, Rik Vandenberghe, Silvy Gabel, Karen Meersmans, Sebastiaan EngelborghsEllen E De Roeck, Kristel Sleegers, Giovanni B Frisoni, Olivier Blin, Jill C Richardson, Régis Bordet, José L Molinuevo, Lorena Rami, Anders Wallin, Petronella Kettunen, Magda Tsolaki, Frans Verhey, Alberto Lléo, Isabel Sala, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Peter Johannsen, Yvonne Freund-Levi, Lutz Frölich, Valerija Dobricic, Cristina Legido-Quigley, Lars Bertram, Frederik Barkhof, Henrik Zetterberg, B Paul Morgan, Johannes Streffer, Pieter Jelle Visser, Simon Lovestone

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

Abstract

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ϵ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

Original language	English
Pages (from-to)	213-225
Number of pages	13
Journal	Journal of Alzheimer's Disease
Volume	74
Issue number	1
Early online date	22 Jan 2020
DOIs	https://doi.org/10.3233/JAD-190434
Publication status	Published - 2020

Bibliographical note

Funding Information:
This research was conducted as part of the EMIF-AD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n\u25E6 115372, resources of which are composed of financial contribution from the European Union\u2019s Seventh Framework Programme (FP7/2007\u20132013) and EFPIA companies\u2019 in-kind contribution. ANH and SL were supported by a MRC Mental Health Data Pathfinder award to the University of Oxford, and by the NIHR Oxford Health Biomedical Research Centre (BRC). FB is supported by the NIHR UCLH biomedical research centre. The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030141179). Cardiff University acknowledge Wellcome Trust support (grant: 104025/Z/14/Z) as part of the research project entitled \u201CWellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer\u2019s Disease\u201D. The views expressed are those of the authors and not necessarily those of the MRC, the NHS, the NIHR or the Department of Health.

Publisher Copyright:
© 2020 - IOS Press and the authors. All rights reserved.

Keywords

Alzheimer’s disease
amyloid-β
biomarkers
plasma
proteomics

Access to Document

10.3233/JAD-190434

Handle.net

Persistent link

Cite this

Westwood, S., Baird, A. L., Anand, S. N., Nevado-Holgado, A. J., Kormilitzin, A., Shi, L., Hye, A., Ashton, N. J., Morgan, A. R., Bos, I., Vos, S. J. B., Baker, S., Buckley, N. J., Ten Kate, M., Scheltens, P., Teunissen, C. E., Vandenberghe, R., Gabel, S., Meersmans, K., ... Lovestone, S. (2020). Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort. Journal of Alzheimer's Disease, 74(1), 213-225. https://doi.org/10.3233/JAD-190434

@article{cb1b09023a7c486db8d1beca290e01a9,

title = "Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort",

abstract = "We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ϵ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.",

keywords = "Alzheimer{\textquoteright}s disease, amyloid-β, biomarkers, plasma, proteomics",

author = "Sarah Westwood and Baird, {Alison L} and Anand, {Sneha N} and Nevado-Holgado, {Alejo J} and Andrey Kormilitzin and Liu Shi and Abdul Hye and Ashton, {Nicholas J} and Morgan, {Angharad R} and Isabelle Bos and Vos, {Stephanie J B} and Susan Baker and Buckley, {Noel J} and {Ten Kate}, Mara and Philip Scheltens and Teunissen, {Charlotte E} and Rik Vandenberghe and Silvy Gabel and Karen Meersmans and Sebastiaan Engelborghs and {De Roeck}, {Ellen E} and Kristel Sleegers and Frisoni, {Giovanni B} and Olivier Blin and Richardson, {Jill C} and R{\'e}gis Bordet and Molinuevo, {Jos{\'e} L} and Lorena Rami and Anders Wallin and Petronella Kettunen and Magda Tsolaki and Frans Verhey and Alberto Ll{\'e}o and Isabel Sala and Julius Popp and Gwendoline Peyratout and Pablo Martinez-Lage and Mikel Tainta and Peter Johannsen and Yvonne Freund-Levi and Lutz Fr{\"o}lich and Valerija Dobricic and Cristina Legido-Quigley and Lars Bertram and Frederik Barkhof and Henrik Zetterberg and Morgan, {B Paul} and Johannes Streffer and Visser, {Pieter Jelle} and Simon Lovestone",

note = "Funding Information: This research was conducted as part of the EMIF-AD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n\u25E6 115372, resources of which are composed of financial contribution from the European Union\u2019s Seventh Framework Programme (FP7/2007\u20132013) and EFPIA companies\u2019 in-kind contribution. ANH and SL were supported by a MRC Mental Health Data Pathfinder award to the University of Oxford, and by the NIHR Oxford Health Biomedical Research Centre (BRC). FB is supported by the NIHR UCLH biomedical research centre. The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030141179). Cardiff University acknowledge Wellcome Trust support (grant: 104025/Z/14/Z) as part of the research project entitled \u201CWellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer\u2019s Disease\u201D. The views expressed are those of the authors and not necessarily those of the MRC, the NHS, the NIHR or the Department of Health. Publisher Copyright: {\textcopyright} 2020 - IOS Press and the authors. All rights reserved.",

year = "2020",

doi = "10.3233/JAD-190434",

language = "English",

volume = "74",

pages = "213--225",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "IOS Press",

number = "1",

}

Westwood, S, Baird, AL, Anand, SN, Nevado-Holgado, AJ, Kormilitzin, A, Shi, L, Hye, A, Ashton, NJ, Morgan, AR, Bos, I, Vos, SJB, Baker, S, Buckley, NJ, Ten Kate, M, Scheltens, P, Teunissen, CE, Vandenberghe, R, Gabel, S, Meersmans, K, Engelborghs, S, De Roeck, EE, Sleegers, K, Frisoni, GB, Blin, O, Richardson, JC, Bordet, R, Molinuevo, JL, Rami, L, Wallin, A, Kettunen, P, Tsolaki, M, Verhey, F, Lléo, A, Sala, I, Popp, J, Peyratout, G, Martinez-Lage, P, Tainta, M, Johannsen, P, Freund-Levi, Y, Frölich, L, Dobricic, V, Legido-Quigley, C, Bertram, L, Barkhof, F, Zetterberg, H, Morgan, BP, Streffer, J, Visser, PJ & Lovestone, S 2020, 'Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort', Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 213-225. https://doi.org/10.3233/JAD-190434

TY - JOUR

T1 - Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort

AU - Westwood, Sarah

AU - Baird, Alison L

AU - Anand, Sneha N

AU - Nevado-Holgado, Alejo J

AU - Kormilitzin, Andrey

AU - Shi, Liu

AU - Hye, Abdul

AU - Ashton, Nicholas J

AU - Morgan, Angharad R

AU - Bos, Isabelle

AU - Vos, Stephanie J B

AU - Baker, Susan

AU - Buckley, Noel J

AU - Ten Kate, Mara

AU - Scheltens, Philip

AU - Teunissen, Charlotte E

AU - Vandenberghe, Rik

AU - Gabel, Silvy

AU - Meersmans, Karen

AU - Engelborghs, Sebastiaan

AU - De Roeck, Ellen E

AU - Sleegers, Kristel

AU - Frisoni, Giovanni B

AU - Blin, Olivier

AU - Richardson, Jill C

AU - Bordet, Régis

AU - Molinuevo, José L

AU - Rami, Lorena

AU - Wallin, Anders

AU - Kettunen, Petronella

AU - Tsolaki, Magda

AU - Verhey, Frans

AU - Lléo, Alberto

AU - Sala, Isabel

AU - Popp, Julius

AU - Peyratout, Gwendoline

AU - Martinez-Lage, Pablo

AU - Tainta, Mikel

AU - Johannsen, Peter

AU - Freund-Levi, Yvonne

AU - Frölich, Lutz

AU - Dobricic, Valerija

AU - Legido-Quigley, Cristina

AU - Bertram, Lars

AU - Barkhof, Frederik

AU - Zetterberg, Henrik

AU - Morgan, B Paul

AU - Streffer, Johannes

AU - Visser, Pieter Jelle

AU - Lovestone, Simon

N1 - Funding Information: This research was conducted as part of the EMIF-AD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n\u25E6 115372, resources of which are composed of financial contribution from the European Union\u2019s Seventh Framework Programme (FP7/2007\u20132013) and EFPIA companies\u2019 in-kind contribution. ANH and SL were supported by a MRC Mental Health Data Pathfinder award to the University of Oxford, and by the NIHR Oxford Health Biomedical Research Centre (BRC). FB is supported by the NIHR UCLH biomedical research centre. The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030141179). Cardiff University acknowledge Wellcome Trust support (grant: 104025/Z/14/Z) as part of the research project entitled \u201CWellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer\u2019s Disease\u201D. The views expressed are those of the authors and not necessarily those of the MRC, the NHS, the NIHR or the Department of Health. Publisher Copyright: © 2020 - IOS Press and the authors. All rights reserved.

PY - 2020

Y1 - 2020

N2 - We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ϵ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

AB - We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ϵ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

KW - Alzheimer’s disease

KW - amyloid-β

KW - biomarkers

KW - plasma

KW - proteomics

UR - http://www.scopus.com/inward/record.url?scp=85082024715&partnerID=8YFLogxK

U2 - 10.3233/JAD-190434

DO - 10.3233/JAD-190434

M3 - Article

C2 - 31985466

SN - 1387-2877

VL - 74

SP - 213

EP - 225

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

IS - 1

ER -

Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort

Abstract

Bibliographical note

Keywords

Access to Document

Handle.net

Other files and links

Fingerprint

Cite this