Inflammatory biomarkers in Alzheimer's disease plasma

Angharad R. Morgan; Samuel Touchard; Claire Leckey; Caroline O'Hagan; Alejo J. Nevado-Holgado; Frederik Barkhof; Lars Bertram; Olivier Blin; Isabelle Bos; Valerija Dobricic; Sebastiaan Engelborghs; Giovanni Frisoni; Lutz Froelich; Silvey Gabel; Peter Johannsen; Petronella Kettunen; Iwona Koszewska; Cristina Legido-Quigley; Alberto Lleo; Pablo Martinez-Lage; Patrizia Mecocci; Karen Meersmans; Jose Luis Molinuevo; Gwendoline Peyratout; Julius Popp; Jill Richardson; Isabel Sala; Philip Scheltens; Johannes Streffer; Hikka Soininen; Mikel Tainta-Cuezva; Charlotte Teunissen; Magda Tsolaki; Rik Vandenberghe; Pieter Jelle Visser; Stephanie Vos; Lars-Olof Wahlund; Anders Wallin; Sarah Westwood; Henrik Zetterberg; Simon Lovestone; B. Paul Morgan; Edward T. Bullmore; Junaid Bhatti; Samuel J. Chamberlain; Marta M. Correia; Anna L. Crofts; Amber Dickinson; Andrew C. Foster; Manfred G. Kitzbichler; NIMA–Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease

doi:10.1016/j.jalz.2019.03.007

Inflammatory biomarkers in Alzheimer's disease plasma

Angharad R. Morgan, Samuel Touchard, Claire Leckey, Caroline O'Hagan, Alejo J. Nevado-Holgado, Frederik Barkhof, Lars Bertram, Olivier Blin, Isabelle Bos, Valerija Dobricic, Sebastiaan Engelborghs, Giovanni Frisoni, Lutz Froelich, Silvey Gabel, Peter Johannsen, Petronella Kettunen, Iwona Koszewska, Cristina Legido-Quigley, Alberto Lleo, Pablo Martinez-LagePatrizia Mecocci, Karen Meersmans, Jose Luis Molinuevo, Gwendoline Peyratout, Julius Popp, Jill Richardson, Isabel Sala, Philip Scheltens, Johannes Streffer, Hikka Soininen, Mikel Tainta-Cuezva, Charlotte Teunissen, Magda Tsolaki, Rik Vandenberghe, Pieter Jelle Visser, Stephanie Vos, Lars-Olof Wahlund, Anders Wallin, Sarah Westwood, Henrik Zetterberg, Simon Lovestone, B. Paul Morgan^*, Edward T. Bullmore, Junaid Bhatti, Samuel J. Chamberlain, Marta M. Correia, Anna L. Crofts, Amber Dickinson, Andrew C. Foster, Manfred G. Kitzbichler, NIMA–Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease

^*Corresponding author for this work

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

36 Downloads (Pure)

Abstract

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers.

Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.

Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOe4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).

Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Original language	English
Pages (from-to)	776-787
Number of pages	12
Journal	Alzheimer's & Dementia
Volume	15
Issue number	6
DOIs	https://doi.org/10.1016/j.jalz.2019.03.007
Publication status	Published - Jun 2019

Keywords

Alzheimer's disease
Biomarker
Plasma
Inflammation
Complement
MILD COGNITIVE IMPAIRMENT
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
GENOME-WIDE ASSOCIATION
IMMUNE-SYSTEM
CEREBROSPINAL-FLUID
IDENTIFIES VARIANTS
FACTOR-H
COMPLEMENT
SERUM
RISK

Access to Document

10.1016/j.jalz.2019.03.007Licence: Unspecified

Full text Final published version, 531 KBLicence: Taverne

Cite this

Morgan, A. R., Touchard, S., Leckey, C., O'Hagan, C., Nevado-Holgado, A. J., Barkhof, F., Bertram, L., Blin, O., Bos, I., Dobricic, V., Engelborghs, S., Frisoni, G., Froelich, L., Gabel, S., Johannsen, P., Kettunen, P., Koszewska, I., Legido-Quigley, C., Lleo, A., ... NIMA–Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease (2019). Inflammatory biomarkers in Alzheimer's disease plasma. Alzheimer's & Dementia, 15(6), 776-787. https://doi.org/10.1016/j.jalz.2019.03.007

@article{8a576608bfe3476f982929c1e23175dd,

title = "Inflammatory biomarkers in Alzheimer's disease plasma",

abstract = "Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a {"}Holy Grail{"} of AD research and intensively sought; however, there are no well-established plasma markers.Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOe4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).",

keywords = "Alzheimer's disease, Biomarker, Plasma, Inflammation, Complement, MILD COGNITIVE IMPAIRMENT, NONSTEROIDAL ANTIINFLAMMATORY DRUGS, GENOME-WIDE ASSOCIATION, IMMUNE-SYSTEM, CEREBROSPINAL-FLUID, IDENTIFIES VARIANTS, FACTOR-H, COMPLEMENT, SERUM, RISK",

author = "Morgan, {Angharad R.} and Samuel Touchard and Claire Leckey and Caroline O'Hagan and Nevado-Holgado, {Alejo J.} and Frederik Barkhof and Lars Bertram and Olivier Blin and Isabelle Bos and Valerija Dobricic and Sebastiaan Engelborghs and Giovanni Frisoni and Lutz Froelich and Silvey Gabel and Peter Johannsen and Petronella Kettunen and Iwona Koszewska and Cristina Legido-Quigley and Alberto Lleo and Pablo Martinez-Lage and Patrizia Mecocci and Karen Meersmans and {Luis Molinuevo}, Jose and Gwendoline Peyratout and Julius Popp and Jill Richardson and Isabel Sala and Philip Scheltens and Johannes Streffer and Hikka Soininen and Mikel Tainta-Cuezva and Charlotte Teunissen and Magda Tsolaki and Rik Vandenberghe and Visser, {Pieter Jelle} and Stephanie Vos and Lars-Olof Wahlund and Anders Wallin and Sarah Westwood and Henrik Zetterberg and Simon Lovestone and Morgan, {B. Paul} and Bullmore, {Edward T.} and Junaid Bhatti and Chamberlain, {Samuel J.} and Correia, {Marta M.} and Crofts, {Anna L.} and Amber Dickinson and Foster, {Andrew C.} and Kitzbichler, {Manfred G.} and {NIMA–Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease}",

note = "Funding Information: B.P.M. is a consultant for GlaxoSmithKline (GSK), Roche, Alexion, and Achillion. F.B. is supported by the NIHR UCLH biomedical research center. S.E. reports research funding from Janssen Pharmaceutica N.V. and ADx Neurosciences (paid to institution). L.F. has received honoraria for consulting or educational lectures, and/or advisory boards from Allergan, Eli Lilly, Avraham Pharma, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, H. Lundbeck A/S, Merck Sharpe & Dohme, Novartis, Pfizer, Piramal Imaging, Pharmatropix, Pharnext, Roche, and Willmar Schwaber. P.M.-L. has received honoraria for lecturing from Lilly, Nutricia, Stada, Schwabbe, General-Electric, and for participating in advisory boards from Biogen, Nutricia, Lilly, General-Electric. J.P. received grants from the Swiss National Science Foundation ( SNF 320030L_141179 ), Fujirebio Europe , Lilly , Ono Pharma , and the Nestl{\'e} Institute of Health Sciences . J.R. was a full-time employee of GSK and is a GSK share holder. P.S. has acquired grant support (for the institution) from Piramal . In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche (Diagnostics). He is PI of studies with Probiodrug and EIP Pharma. S.V . receives research support from the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development), Janssen Pharmaceutica N.V. , and the Alzheimer's Association . Funding Information: B.P.M. is a consultant for GlaxoSmithKline (GSK), Roche, Alexion, and Achillion. F.B. is supported by the NIHR UCLH biomedical research center. S.E. reports research funding from Janssen Pharmaceutica N.V. and ADx Neurosciences (paid to institution). L.F. has received honoraria for consulting or educational lectures, and/or advisory boards from Allergan, Eli Lilly, Avraham Pharma, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, H. Lundbeck A/S, Merck Sharpe & Dohme, Novartis, Pfizer, Piramal Imaging, Pharmatropix, Pharnext, Roche, and Willmar Schwaber. P.M.-L. has received honoraria for lecturing from Lilly, Nutricia, Stada, Schwabbe, General-Electric, and for participating in advisory boards from Biogen, Nutricia, Lilly, General-Electric. J.P. received grants from the Swiss National Science Foundation (SNF 320030L_141179), Fujirebio Europe, Lilly, Ono Pharma, and the Nestl? Institute of Health Sciences. J.R. was a full-time employee of GSK and is a GSK share holder. P.S. has acquired grant support (for the institution) from Piramal. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche (Diagnostics). He is PI of studies with Probiodrug and EIP Pharma. S.V. receives research support from the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development), Janssen Pharmaceutica N.V., and the Alzheimer's Association.This publication incorporates results from the research project entitled ?Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease? which is funded by a grant from the Wellcome Trust (grant number: 104025/Z/14/Z). A complete list of Consortium members is given in the Annex. The AddNeuroMed and DCR plasma samples were provided by the NIHR Biomedical Research Centre and NIHR Dementia Biomedical Research Unit hosted at Kings College London and South London and Maudsley NHS Foundation Trust and funded by the National Institute for Health Research under its Biomedical Research Centers initiative. Authors' contributions: B.P.M. S.L. A.R.M. S.T. and A.J.N.-H. contributed to study design. A.R.M. C.L. and C.O.'H. processed samples and conducted all assays. S.T. and A.J.N.-H. conducted data processing and statistical analyses. B.P.M. A.R.M. S.L. and S.T. contributed to the writing of the paper. Other authors contributed to the EMIF-AD MBD cohort. All authors read and approved the final manuscript. Annex: NIMA?Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease. Consortium members?Part 1: Cambridge: Edward T. Bullmore (MD, PI, EC)1,2,11, Junaid Bhatti1, Samuel J. Chamberlain1,2, Marta M. Correia1,12, Anna L. Crofts1, Amber Dickinson*, Andrew C. Foster*, Manfred G. Kitzbichler1, Clare Knight*, Mary-Ellen Lynall1, Christina Maurice1, Ciara O'Donnell1, Linda J. Pointon1, Peter St George Hyslop1,13,14, Lorinda Turner31, Petra Vertes1, Barry Widmer1, Guy B. Williams.1,14, Cardiff: B. Paul Morgan (PI)15, Claire A. Leckey15, Angharad R. Morgan*, Caroline O'Hagan*, Samuel Touchard.15, Glasgow: Jonathan Cavanagh (PI, EC)3, Catherine Deith*, Scott Farmer16, John McClean16, Alison McColl3, Andrew McPherson*, Paul Scouller*, Murray Sutherland.16, Independent advisor: H.W.G.M. (Erik) Boddeke (EC).17, GSK: Jill C. Richardson (EC)18, Shahid Khan11, Phil Murphy19, Christine A. Parker19, Jai Patel.11, Janssen: Declan Jones (EC)6, Peter de Boer4, John Kemp4, Wayne C. Drevets6, Jeffrey S. Nye (deceased), Gayle Wittenberg6, John Isaac6, Anindya Bhattacharya6, Nick Carruthers6, Hartmuth Kolb.6, Kings College London: Carmine M. Pariante (PI)10, Federico Turkheimer (PI)20, Gareth J. Barker20, Heidi Byrom10, Diana Cash20, Annamaria Cattaneo10, Antony Gee20, Caitlin Hastings10, Nicole Mariani10, Anna McLaughlin10, Valeria Mondelli10, Maria Nettis10, Naghmeh Nikkheslat10, Karen Randall20, Hannah Sheridan*, Camilla Simmons20, Nisha Singh20, Victoria Van Loo*, Marta Vicente-Rodriguez20, Tobias C. Wood20, Courtney Worrell*, Zuzanna Zajkowska.*, Lundbeck: Niels Plath (EC)21, Jan Egebjerg21, Hans Eriksson21, Francois Gastambide21, Karen Husted Adams21, Ross Jeggo21, Christian Thomsen21, Jan Torleif Pederson21, Brian Campbell*, Thomas M?ller*, Bob Nelson*, Stevin Zorn.*, University of Texas (subcontracted to Lundbeck): Jason O'Connor.22, Oxford: Mary Jane Attenburrow (PI)7,23, Alison Baird, Jithen Benjamin23, Stuart Clare25, Philip Cowen7, I-Shu (Dante) Huang24, Samuel Hurley*, Helen Jones23, Simon Lovestone7,(AD, PI, EC) Francisca Mada*, Alejo Nevado-Holgado7, Akintayo Oladejo*, Elena Ribe7, Katy Smith23, Anviti Vyas.*, Pfizer: Zoe Hughes (EC)*, Rita Balice-Gordon*, James Duerr*, Justin R. Piro*, Jonathan Sporn.*, Southampton: V. Hugh Perry (PI)27, Madeleine Cleal*, Gemma Fryatt27, Diego Gomez-Nicola27, Renzo Mancuso32, Richard Reynolds.27, Sussex: Neil A. Harrison (PI, EC)28, Mara Cercignani28, Charlotte L. Clarke28, Elizabeth Hoskins*, Charmaine Kohn*, Rosemary Murray*, Lauren Wilcock29, Dominika Wlazly30, University of Toronto (sub-contracted to Cambridge): Howard Mount.13, MD = mood disorders workpackages lead; AD = Alzheimer's disease workpackages lead; PI = principal investigator; EC = executive committee member. 1 Department of Psychiatry, School of Clinical Medicine, University of Cambridge, CB2 0SZ, UK. 2 Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, CB21 5EF, UK. 3 Sackler Centre, Institute of Health & Wellbeing, University of Glasgow, Sir Graeme Davies Building, Glasgow, G12 8 TA, UK. 4 Neuroscience, Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium. 5 The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT, UK. 6 Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, 08560, USA. 7 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK. 8 Brighton & Sussex Medical School, University of Sussex, Brighton, BN1 9RR, UK. 9 Sussex Partnership NHS Foundation Trust, Swandean, BN13 3EP, UK. 10 Kings College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London, SE5 9RT, UK. 11 Immuno-Psychiatry, Immuno-Inflammation Therapeutic Area Unit, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK. 12 MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 7EF, UK. 13 Tanz Centre for Research in Neurodegenerative Diseases, 60 Leonard Avenue, Toronto, ON M5T 2S8 Canada. 14 Department of Clinical Neurosciences, University of Cambridge, CB2 0SZ, UK. 15 Cardiff University, Cardiff CF10 3AT, UK. 16 NHS Greater Glasgow and Clyde, 1055 Great Western Rd, Glasgow G12 0XH, UK. 17 University of Groningen, 9712 CP Groningen, Netherlands. 18 Neurosciences Virtual PoC DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK. 19 Experimental Medicine Imaging, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK. 20 King's College London, Department of Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London SE5 8AF, UK. 21 H. Lundbeck A/S Ottiliavej 9, 2500, Valby, Denmark. 22 University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA. 23 NIHR Oxford cognitive health Clinical Research Facility, Warneford Hospital, Oxford, OX3 7JX, UK. 24 The Kennedy Institute of Rheumatology, Roosevelt Dr, Oxford OX3 7FY, UK. 25 Oxford Centre for Functional MRI of the Brain, John Radcliffe Hospital, Oxford OX3 9DU, UK. 26 Pfizer, Inc, 1 Portland Street, Cambridge MA, USA. 27 Centre for Biological Sciences, University of Southampton, Southampton, UK. 28 Clinical Imaging Sciences Centre (CISC), University of Sussex, Brighton, BN1 9RR, UK. 29 Sussex Partnership NHS Foundation Trust, Nevill Avenue, Hove BN3 7HZ, UK. 30 Brighton & Sussex University Hospitals NHS Trust, Brighton BN2 5BE, UK. 31 Department of Medicine, School of Clinical Medicine, University of Cambridge, CB2 0SZ, UK. 32 VIB-KU Leuven Center for Brain & Disease Research, Campus Gasthuisberg, Herestraat 49, bus 602, 3000 Leuven, Belgium. ?Former consortium members. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = jun,

doi = "10.1016/j.jalz.2019.03.007",

language = "English",

volume = "15",

pages = "776--787",

journal = "Alzheimer's & Dementia",

issn = "1552-5260",

publisher = "Elsevier Science",

number = "6",

}

Morgan, AR, Touchard, S, Leckey, C, O'Hagan, C, Nevado-Holgado, AJ, Barkhof, F, Bertram, L, Blin, O, Bos, I, Dobricic, V, Engelborghs, S, Frisoni, G, Froelich, L, Gabel, S, Johannsen, P, Kettunen, P, Koszewska, I, Legido-Quigley, C, Lleo, A, Martinez-Lage, P, Mecocci, P, Meersmans, K, Luis Molinuevo, J, Peyratout, G, Popp, J, Richardson, J, Sala, I, Scheltens, P, Streffer, J, Soininen, H, Tainta-Cuezva, M, Teunissen, C, Tsolaki, M, Vandenberghe, R, Visser, PJ, Vos, S, Wahlund, L-O, Wallin, A, Westwood, S, Zetterberg, H, Lovestone, S, Morgan, BP, Bullmore, ET, Bhatti, J, Chamberlain, SJ, Correia, MM, Crofts, AL, Dickinson, A, Foster, AC, Kitzbichler, MG & NIMA–Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease 2019, 'Inflammatory biomarkers in Alzheimer's disease plasma', Alzheimer's & Dementia, vol. 15, no. 6, pp. 776-787. https://doi.org/10.1016/j.jalz.2019.03.007

TY - JOUR

T1 - Inflammatory biomarkers in Alzheimer's disease plasma

AU - Morgan, Angharad R.

AU - Touchard, Samuel

AU - Leckey, Claire

AU - O'Hagan, Caroline

AU - Nevado-Holgado, Alejo J.

AU - Barkhof, Frederik

AU - Bertram, Lars

AU - Blin, Olivier

AU - Bos, Isabelle

AU - Dobricic, Valerija

AU - Engelborghs, Sebastiaan

AU - Frisoni, Giovanni

AU - Froelich, Lutz

AU - Gabel, Silvey

AU - Johannsen, Peter

AU - Kettunen, Petronella

AU - Koszewska, Iwona

AU - Legido-Quigley, Cristina

AU - Lleo, Alberto

AU - Martinez-Lage, Pablo

AU - Mecocci, Patrizia

AU - Meersmans, Karen

AU - Luis Molinuevo, Jose

AU - Peyratout, Gwendoline

AU - Popp, Julius

AU - Richardson, Jill

AU - Sala, Isabel

AU - Scheltens, Philip

AU - Streffer, Johannes

AU - Soininen, Hikka

AU - Tainta-Cuezva, Mikel

AU - Teunissen, Charlotte

AU - Tsolaki, Magda

AU - Vandenberghe, Rik

AU - Visser, Pieter Jelle

AU - Vos, Stephanie

AU - Wahlund, Lars-Olof

AU - Wallin, Anders

AU - Westwood, Sarah

AU - Zetterberg, Henrik

AU - Lovestone, Simon

AU - Morgan, B. Paul

AU - Bullmore, Edward T.

AU - Bhatti, Junaid

AU - Chamberlain, Samuel J.

AU - Correia, Marta M.

AU - Crofts, Anna L.

AU - Dickinson, Amber

AU - Foster, Andrew C.

AU - Kitzbichler, Manfred G.

AU - NIMA–Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease

N1 - Funding Information: B.P.M. is a consultant for GlaxoSmithKline (GSK), Roche, Alexion, and Achillion. F.B. is supported by the NIHR UCLH biomedical research center. S.E. reports research funding from Janssen Pharmaceutica N.V. and ADx Neurosciences (paid to institution). L.F. has received honoraria for consulting or educational lectures, and/or advisory boards from Allergan, Eli Lilly, Avraham Pharma, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, H. Lundbeck A/S, Merck Sharpe & Dohme, Novartis, Pfizer, Piramal Imaging, Pharmatropix, Pharnext, Roche, and Willmar Schwaber. P.M.-L. has received honoraria for lecturing from Lilly, Nutricia, Stada, Schwabbe, General-Electric, and for participating in advisory boards from Biogen, Nutricia, Lilly, General-Electric. J.P. received grants from the Swiss National Science Foundation ( SNF 320030L_141179 ), Fujirebio Europe , Lilly , Ono Pharma , and the Nestlé Institute of Health Sciences . J.R. was a full-time employee of GSK and is a GSK share holder. P.S. has acquired grant support (for the institution) from Piramal . In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche (Diagnostics). He is PI of studies with Probiodrug and EIP Pharma. S.V . receives research support from the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development), Janssen Pharmaceutica N.V. , and the Alzheimer's Association . Funding Information: B.P.M. is a consultant for GlaxoSmithKline (GSK), Roche, Alexion, and Achillion. F.B. is supported by the NIHR UCLH biomedical research center. S.E. reports research funding from Janssen Pharmaceutica N.V. and ADx Neurosciences (paid to institution). L.F. has received honoraria for consulting or educational lectures, and/or advisory boards from Allergan, Eli Lilly, Avraham Pharma, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, H. Lundbeck A/S, Merck Sharpe & Dohme, Novartis, Pfizer, Piramal Imaging, Pharmatropix, Pharnext, Roche, and Willmar Schwaber. P.M.-L. has received honoraria for lecturing from Lilly, Nutricia, Stada, Schwabbe, General-Electric, and for participating in advisory boards from Biogen, Nutricia, Lilly, General-Electric. J.P. received grants from the Swiss National Science Foundation (SNF 320030L_141179), Fujirebio Europe, Lilly, Ono Pharma, and the Nestl? Institute of Health Sciences. J.R. was a full-time employee of GSK and is a GSK share holder. P.S. has acquired grant support (for the institution) from Piramal. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche (Diagnostics). He is PI of studies with Probiodrug and EIP Pharma. S.V. receives research support from the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development), Janssen Pharmaceutica N.V., and the Alzheimer's Association.This publication incorporates results from the research project entitled ?Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease? which is funded by a grant from the Wellcome Trust (grant number: 104025/Z/14/Z). A complete list of Consortium members is given in the Annex. The AddNeuroMed and DCR plasma samples were provided by the NIHR Biomedical Research Centre and NIHR Dementia Biomedical Research Unit hosted at Kings College London and South London and Maudsley NHS Foundation Trust and funded by the National Institute for Health Research under its Biomedical Research Centers initiative. Authors' contributions: B.P.M. S.L. A.R.M. S.T. and A.J.N.-H. contributed to study design. A.R.M. C.L. and C.O.'H. processed samples and conducted all assays. S.T. and A.J.N.-H. conducted data processing and statistical analyses. B.P.M. A.R.M. S.L. and S.T. contributed to the writing of the paper. Other authors contributed to the EMIF-AD MBD cohort. All authors read and approved the final manuscript. Annex: NIMA?Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease. Consortium members?Part 1: Cambridge: Edward T. Bullmore (MD, PI, EC)1,2,11, Junaid Bhatti1, Samuel J. Chamberlain1,2, Marta M. Correia1,12, Anna L. Crofts1, Amber Dickinson*, Andrew C. Foster*, Manfred G. Kitzbichler1, Clare Knight*, Mary-Ellen Lynall1, Christina Maurice1, Ciara O'Donnell1, Linda J. Pointon1, Peter St George Hyslop1,13,14, Lorinda Turner31, Petra Vertes1, Barry Widmer1, Guy B. Williams.1,14, Cardiff: B. Paul Morgan (PI)15, Claire A. Leckey15, Angharad R. Morgan*, Caroline O'Hagan*, Samuel Touchard.15, Glasgow: Jonathan Cavanagh (PI, EC)3, Catherine Deith*, Scott Farmer16, John McClean16, Alison McColl3, Andrew McPherson*, Paul Scouller*, Murray Sutherland.16, Independent advisor: H.W.G.M. (Erik) Boddeke (EC).17, GSK: Jill C. Richardson (EC)18, Shahid Khan11, Phil Murphy19, Christine A. Parker19, Jai Patel.11, Janssen: Declan Jones (EC)6, Peter de Boer4, John Kemp4, Wayne C. Drevets6, Jeffrey S. Nye (deceased), Gayle Wittenberg6, John Isaac6, Anindya Bhattacharya6, Nick Carruthers6, Hartmuth Kolb.6, Kings College London: Carmine M. Pariante (PI)10, Federico Turkheimer (PI)20, Gareth J. Barker20, Heidi Byrom10, Diana Cash20, Annamaria Cattaneo10, Antony Gee20, Caitlin Hastings10, Nicole Mariani10, Anna McLaughlin10, Valeria Mondelli10, Maria Nettis10, Naghmeh Nikkheslat10, Karen Randall20, Hannah Sheridan*, Camilla Simmons20, Nisha Singh20, Victoria Van Loo*, Marta Vicente-Rodriguez20, Tobias C. Wood20, Courtney Worrell*, Zuzanna Zajkowska.*, Lundbeck: Niels Plath (EC)21, Jan Egebjerg21, Hans Eriksson21, Francois Gastambide21, Karen Husted Adams21, Ross Jeggo21, Christian Thomsen21, Jan Torleif Pederson21, Brian Campbell*, Thomas M?ller*, Bob Nelson*, Stevin Zorn.*, University of Texas (subcontracted to Lundbeck): Jason O'Connor.22, Oxford: Mary Jane Attenburrow (PI)7,23, Alison Baird, Jithen Benjamin23, Stuart Clare25, Philip Cowen7, I-Shu (Dante) Huang24, Samuel Hurley*, Helen Jones23, Simon Lovestone7,(AD, PI, EC) Francisca Mada*, Alejo Nevado-Holgado7, Akintayo Oladejo*, Elena Ribe7, Katy Smith23, Anviti Vyas.*, Pfizer: Zoe Hughes (EC)*, Rita Balice-Gordon*, James Duerr*, Justin R. Piro*, Jonathan Sporn.*, Southampton: V. Hugh Perry (PI)27, Madeleine Cleal*, Gemma Fryatt27, Diego Gomez-Nicola27, Renzo Mancuso32, Richard Reynolds.27, Sussex: Neil A. Harrison (PI, EC)28, Mara Cercignani28, Charlotte L. Clarke28, Elizabeth Hoskins*, Charmaine Kohn*, Rosemary Murray*, Lauren Wilcock29, Dominika Wlazly30, University of Toronto (sub-contracted to Cambridge): Howard Mount.13, MD = mood disorders workpackages lead; AD = Alzheimer's disease workpackages lead; PI = principal investigator; EC = executive committee member. 1 Department of Psychiatry, School of Clinical Medicine, University of Cambridge, CB2 0SZ, UK. 2 Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, CB21 5EF, UK. 3 Sackler Centre, Institute of Health & Wellbeing, University of Glasgow, Sir Graeme Davies Building, Glasgow, G12 8 TA, UK. 4 Neuroscience, Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium. 5 The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT, UK. 6 Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, 08560, USA. 7 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK. 8 Brighton & Sussex Medical School, University of Sussex, Brighton, BN1 9RR, UK. 9 Sussex Partnership NHS Foundation Trust, Swandean, BN13 3EP, UK. 10 Kings College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London, SE5 9RT, UK. 11 Immuno-Psychiatry, Immuno-Inflammation Therapeutic Area Unit, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK. 12 MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 7EF, UK. 13 Tanz Centre for Research in Neurodegenerative Diseases, 60 Leonard Avenue, Toronto, ON M5T 2S8 Canada. 14 Department of Clinical Neurosciences, University of Cambridge, CB2 0SZ, UK. 15 Cardiff University, Cardiff CF10 3AT, UK. 16 NHS Greater Glasgow and Clyde, 1055 Great Western Rd, Glasgow G12 0XH, UK. 17 University of Groningen, 9712 CP Groningen, Netherlands. 18 Neurosciences Virtual PoC DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK. 19 Experimental Medicine Imaging, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK. 20 King's College London, Department of Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London SE5 8AF, UK. 21 H. Lundbeck A/S Ottiliavej 9, 2500, Valby, Denmark. 22 University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA. 23 NIHR Oxford cognitive health Clinical Research Facility, Warneford Hospital, Oxford, OX3 7JX, UK. 24 The Kennedy Institute of Rheumatology, Roosevelt Dr, Oxford OX3 7FY, UK. 25 Oxford Centre for Functional MRI of the Brain, John Radcliffe Hospital, Oxford OX3 9DU, UK. 26 Pfizer, Inc, 1 Portland Street, Cambridge MA, USA. 27 Centre for Biological Sciences, University of Southampton, Southampton, UK. 28 Clinical Imaging Sciences Centre (CISC), University of Sussex, Brighton, BN1 9RR, UK. 29 Sussex Partnership NHS Foundation Trust, Nevill Avenue, Hove BN3 7HZ, UK. 30 Brighton & Sussex University Hospitals NHS Trust, Brighton BN2 5BE, UK. 31 Department of Medicine, School of Clinical Medicine, University of Cambridge, CB2 0SZ, UK. 32 VIB-KU Leuven Center for Brain & Disease Research, Campus Gasthuisberg, Herestraat 49, bus 602, 3000 Leuven, Belgium. ?Former consortium members. Publisher Copyright: © 2019 The Authors

PY - 2019/6

Y1 - 2019/6

N2 - Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers.Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOe4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

AB - Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers.Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOe4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

KW - Alzheimer's disease

KW - Biomarker

KW - Plasma

KW - Inflammation

KW - Complement

KW - MILD COGNITIVE IMPAIRMENT

KW - NONSTEROIDAL ANTIINFLAMMATORY DRUGS

KW - GENOME-WIDE ASSOCIATION

KW - IMMUNE-SYSTEM

KW - CEREBROSPINAL-FLUID

KW - IDENTIFIES VARIANTS

KW - FACTOR-H

KW - COMPLEMENT

KW - SERUM

KW - RISK

U2 - 10.1016/j.jalz.2019.03.007

DO - 10.1016/j.jalz.2019.03.007

M3 - Article

C2 - 31047856

SN - 1552-5260

VL - 15

SP - 776

EP - 787

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

IS - 6

ER -