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J Alzheimers Dis. 2020 Jan 22. doi: 10.3233/JAD-190434. [Epub ahead of print]

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

Author information

1
Department of Psychiatry, University of Oxford, UK.
2
Maurice Wohl Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
3
Department of Psychiatry and Neurochemistry, University of Gothenburg, Mölndal, Sweden.
4
Wallenberg Centre for Molecular & Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
5
Dementia Research Institute Cardiff, Cardiff University, Cardiff, UK.
6
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
7
Janssen R&D, Titusville, NJ, USA.
8
Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands.
9
University Hospital Leuven, Leuven, Belgium.
10
Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Belgium.
11
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, University of Antwerp, Antwerp, Belgium.
12
Center for Neurosciences, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
13
Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Belgium.
14
University of Geneva, Geneva, Switzerland.
15
IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
16
AIX Marseille University, INS, Ap-Hm, Marseille, France.
17
Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.
18
University of Lille, Inserm, CHU Lille, France.
19
Alzheimer's Disease & Other Cognitive Disorders Unit, Hopsital Clínic-IDIBAPS, Barcelona, Spain.
20
Barcelona Beta Brain Research Center, Unversitat Pompeu Fabra, Barcelona, Spain.
21
Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
22
1st Department of Neurology, AHEPA University Hospital, Makedonia, Thessaloniki, Greece.
23
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
24
Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
25
University Hospital of Lausanne, Lausanne, Switzerland.
26
Geriatric Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Geneva, Switzerland.
27
CITA-Alzheimer Foundation, San Sebastian, Spain.
28
Danish Dementia Research Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
29
Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, and Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
30
Department of Geriatric Psychiatry, Zentralinstitut für Seelische Gesundheit, University of Heidelberg, Mannheim, Germany.
31
Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany.
32
Kings College London, London, UK.
33
The Systems Medicine Group, Steno Diabetes Center, Gentofte, Denmark.
34
Department of Psychology, University of Oslo, Oslo, Norway.
35
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherland.
36
UCL Institutes of Neurology and Healthcare Engineering, London, UK.
37
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
38
UK Dementia Research Institute at UCL, London, UK.
39
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
40
UCB, Braine-l'Alleud, Belgium, formerly Janssen R&D, LLC. Beerse, Belgium at the Time of Study Conduct.
41
Janssen R&D, UK formerly affiliation (1) at the Time of the Study Conduct.

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 ɛ4 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’s disease; amyloid-β; biomarkers; plasma; proteomics

PMID:
31985466
DOI:
10.3233/JAD-190434

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