Replication study of plasma proteins relating to Alzheimer's pathology

Liu Shi; Laura M. Winchester; Sarah Westwood; Alison L. Baird; Sneha N. Anand; Noel J. Buckley; Abdul Hye; Nicholas J. Ashton; Isabelle Bos; Stephanie J.B. Vos; 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; Frederik Barkhof; Ulf Andreasson; Kaj Blennow; Henrik Zetterberg; Johannes Streffer; Christina M. Lill; Lars Bertram; Pieter Jelle Visser; Hartmuth C. Kolb; Vaibhav A. Narayan; Simon Lovestone; Alejo J. Nevado-Holgado

doi:10.1002/alz.12322

Replication study of plasma proteins relating to Alzheimer's pathology

Liu Shi^*
, Laura M. Winchester
, Sarah Westwood
, Alison L. Baird
, Sneha N. Anand
, Noel J. Buckley
, Abdul Hye
, Nicholas J. Ashton
, Isabelle Bos
, Stephanie J.B. Vos
, 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, Frederik Barkhof, Ulf Andreasson, Kaj Blennow, Henrik Zetterberg, Johannes Streffer, Christina M. Lill, Lars Bertram, Pieter Jelle Visser, Hartmuth C. Kolb, Vaibhav A. Narayan, Simon Lovestone, Alejo J. Nevado-Holgado

^*Corresponding author for this work

University of Oxford
Learning Disability Psychiatry Department
King's College London
Department of Psychiatry and Neurochemistry
Sahlgrenska Academy
Sahlgrenska University Hospital
Maastricht University
VU University Medical Center
AMC Academic Medical Center
University Hospitals Leuven
KU Leuven
University of Antwerp
Universitair Ziekenhuis Brussel
Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken
VIB Flanders Institute for Biotechnology
Global Health Institute
IRCCS Fatebenefratelli
Aix-Marseille University
GSK GlaxoSmithKline Research & Development Ltd
Institut Pasteur de Lille
IDIBAPS August Pi i Sunyer Biomedical Research Institute
Fundació Pasqual Maragall
AHEPA University Hospital
Hosp Santa Creu & Sant Pau, Hospital of Santa Creu i Sant Pau, Serv Reumatol
Centre Hospitalier Universitaire Vaudois
Geneva University Hospitals
CITA-Alzheimer Foundation
Rigshospitalet
Karolinska Institute
Heidelberg University
Institut für Integrative und ExperimentelleGenomik
Systems Medicine Group
Steno Diabetes Center
VU University Hospital
UCL University College London
Janssen Research & Development LLC
University Hospital Schleswig- Holstein
Imperial College London
University of Oslo
Janssen R&D

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

18 Citations (Scopus)

Abstract

Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the “ATN” (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and “N” varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.

Original language	English
Pages (from-to)	1452-1464
Number of pages	13
Journal	Alzheimer's and Dementia
Volume	17
Issue number	9
Early online date	31 Mar 2021
DOIs	https://doi.org/10.1002/alz.12322
Publication status	Published - Sept 2021

Keywords

Alzheimer's disease
ATN framework
biomarker
dementia
network analysis
plasma proteomics
replication

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10.1002/alz.12322

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Shi, L., Winchester, L. M., Westwood, S., Baird, A. L., Anand, S. N., Buckley, N. J., Hye, A., Ashton, N. J., Bos, I., Vos, S. J. B., Kate, M. T., Scheltens, P., Teunissen, C. E., Vandenberghe, R., Gabel, S., Meersmans, K., Engelborghs, S., De Roeck, E. E., Sleegers, K., ... Nevado-Holgado, A. J. (2021). Replication study of plasma proteins relating to Alzheimer's pathology. Alzheimer's and Dementia, 17(9), 1452-1464. https://doi.org/10.1002/alz.12322

@article{2a85249c58fb48f5898dd3597313b0aa,

title = "Replication study of plasma proteins relating to Alzheimer's pathology",

abstract = "Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the “ATN” (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and “N” varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.",

keywords = "Alzheimer's disease, ATN framework, biomarker, dementia, network analysis, plasma proteomics, replication",

author = "Liu Shi and Winchester, \{Laura M.\} and Sarah Westwood and Baird, \{Alison L.\} and Anand, \{Sneha N.\} and Buckley, \{Noel J.\} and Abdul Hye and Ashton, \{Nicholas J.\} and Isabelle Bos and Vos, \{Stephanie J.B.\} and Kate, \{Mara ten\} 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 Frederik Barkhof and Ulf Andreasson and Kaj Blennow and Henrik Zetterberg and Johannes Streffer and Lill, \{Christina M.\} and Lars Bertram and Visser, \{Pieter Jelle\} and Kolb, \{Hartmuth C.\} and Narayan, \{Vaibhav A.\} and Simon Lovestone and Nevado-Holgado, \{Alejo J.\}",

note = "Funding Information: This research was conducted as part of the EMIF-AD MBD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n? 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies? in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract \# 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers \#11020, \#13007, and \#15005). RV is a senior clinical investigator of the Flemish Research Foundation (FWO). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). We acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIB-CMN is funded in part by the University of Antwerp Research Fund. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (\#2018-02532); the European Research Council (\#681712); Swedish State Support for Clinical Research (\#ALFGBG-720931); the Alzheimer Drug Discovery Foundation (ADDF), USA (\#201809-2016862); and the UK Dementia Research Institute at UCL. FB is supported by the NIHR biomedical research center at UCLH. Publisher Copyright: {\textcopyright} 2021 the Alzheimer's Association",

year = "2021",

month = sep,

doi = "10.1002/alz.12322",

language = "English",

volume = "17",

pages = "1452--1464",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc.",

number = "9",

}

Shi, L, Winchester, LM, Westwood, S, Baird, AL, Anand, SN, Buckley, NJ, Hye, A , Ashton, NJ, Bos, I, Vos, SJB, Kate, MT, 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, Barkhof, F, Andreasson, U, Blennow, K, Zetterberg, H, Streffer, J, Lill, CM, Bertram, L, Visser, PJ, Kolb, HC, Narayan, VA, Lovestone, S & Nevado-Holgado, AJ 2021, 'Replication study of plasma proteins relating to Alzheimer's pathology', Alzheimer's and Dementia, vol. 17, no. 9, pp. 1452-1464. https://doi.org/10.1002/alz.12322

TY - JOUR

T1 - Replication study of plasma proteins relating to Alzheimer's pathology

AU - Shi, Liu

AU - Winchester, Laura M.

AU - Westwood, Sarah

AU - Baird, Alison L.

AU - Anand, Sneha N.

AU - Buckley, Noel J.

AU - Hye, Abdul

AU - Ashton, Nicholas J.

AU - Bos, Isabelle

AU - Vos, Stephanie J.B.

AU - Kate, Mara ten

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 - Barkhof, Frederik

AU - Andreasson, Ulf

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Streffer, Johannes

AU - Lill, Christina M.

AU - Bertram, Lars

AU - Visser, Pieter Jelle

AU - Kolb, Hartmuth C.

AU - Narayan, Vaibhav A.

AU - Lovestone, Simon

AU - Nevado-Holgado, Alejo J.

N1 - Funding Information: This research was conducted as part of the EMIF-AD MBD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n? 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies? in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007, and #15005). RV is a senior clinical investigator of the Flemish Research Foundation (FWO). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). We acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIB-CMN is funded in part by the University of Antwerp Research Fund. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532); the European Research Council (#681712); Swedish State Support for Clinical Research (#ALFGBG-720931); the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862); and the UK Dementia Research Institute at UCL. FB is supported by the NIHR biomedical research center at UCLH. Publisher Copyright: © 2021 the Alzheimer's Association

PY - 2021/9

Y1 - 2021/9

N2 - Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the “ATN” (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and “N” varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.

AB - Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the “ATN” (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and “N” varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.

KW - Alzheimer's disease

KW - ATN framework

KW - biomarker

KW - dementia

KW - network analysis

KW - plasma proteomics

KW - replication

UR - https://www.scopus.com/pages/publications/85103432126

U2 - 10.1002/alz.12322

DO - 10.1002/alz.12322

M3 - Article

AN - SCOPUS:85103432126

SN - 1552-5260

VL - 17

SP - 1452

EP - 1464

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 9

ER -

Replication study of plasma proteins relating to Alzheimer's pathology

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