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Alzheimers Res Ther. 2018 Jul 6;10(1):64. doi: 10.1186/s13195-018-0396-5.

The EMIF-AD Multimodal Biomarker Discovery study: design, methods and cohort characteristics.

Author information

1
Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands. isabelle.bos@maastrichtuniversity.nl.
2
Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Universiteitssingel 40, Box 34, P.O. Box 616, 6200, MD, Maastricht, the Netherlands. isabelle.bos@maastrichtuniversity.nl.
3
Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
4
University Hospital Leuven, Leuven, Belgium.
5
Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
6
Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
7
Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium.
8
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
9
University of Antwerp, Antwerp, Belgium.
10
University of Geneva, Geneva, Switzerland.
11
IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
12
Alzheimer's Disease & Other Cognitive Disorders Unit, Hospital Clínic-IDIBAPS, Barcelona, Spain.
13
Barcelona Beta Brain Research Center, Fundació Pasqual Maragall, Barcelona, Spain.
14
Institute of Neuroscience and Physiology, Moelndal, Sweden.
15
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
16
Geriatric Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Geneva, Switzerland.
17
Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
18
Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
19
University of Oxford, Oxford, UK.
20
King's College London, London, UK.
21
NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
22
Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, UK.
23
NIHR University College London Hospitals Biomedical Research Centre, London, UK.
24
Neurodegenerative Brain Diseases Group, VIB-Department of Molecular Genetics, Antwerp, Belgium.
25
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
26
Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
27
School of Public Health, Imperial College London, London, UK.
28
Department of Psychology, University of Oslo, Oslo, Norway.
29
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
30
Department of Psychiatry and Neurochemistry, University of Gothenburg, Mölndal, Sweden.
31
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
32
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
33
UK Dementia Research Institute, London, UK.
34
Experimental Medicine, Janssen Pharmaceutical Companies, Beerse, Belgium.

Abstract

BACKGROUND:

There is an urgent need for novel, noninvasive biomarkers to diagnose Alzheimer's disease (AD) in the predementia stages and to predict the rate of decline. Therefore, we set up the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study. In this report we describe the design of the study, the methods used and the characteristics of the participants.

METHODS:

Participants were selected from existing prospective multicenter and single-center European studies. Inclusion criteria were having normal cognition (NC) or a diagnosis of mild cognitive impairment (MCI) or AD-type dementia at baseline, age above 50 years, known amyloid-beta (Aβ) status, availability of cognitive test results and at least two of the following materials: plasma, DNA, magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF). Targeted and untargeted metabolomic and proteomic analyses were performed in plasma, and targeted and untargeted proteomics were performed in CSF. Genome-wide SNP genotyping, next-generation sequencing and methylation profiling were conducted in DNA. Visual rating and volumetric measures were assessed on MRI. Baseline characteristics were analyzed using ANOVA or chi-square, rate of decline analyzed by linear mixed modeling.

RESULTS:

We included 1221 individuals (NC n = 492, MCI n = 527, AD-type dementia n = 202) with a mean age of 67.9 (SD 8.3) years. The percentage Aβ+ was 26% in the NC, 58% in the MCI, and 87% in the AD-type dementia groups. Plasma samples were available for 1189 (97%) subjects, DNA samples for 929 (76%) subjects, MRI scans for 862 (71%) subjects and CSF samples for 767 (63%) subjects. For 759 (62%) individuals, clinical follow-up data were available. In each diagnostic group, the APOE ε4 allele was more frequent amongst Aβ+ individuals (p < 0.001). Only in MCI was there a difference in baseline Mini Mental State Examination (MMSE) score between the A groups (p < 0.001). Aβ+ had a faster rate of decline on the MMSE during follow-up in the NC (p < 0.001) and MCI (p < 0.001) groups.

CONCLUSIONS:

The characteristics of this large cohort of elderly subjects at various cognitive stages confirm the central roles of Aβ and APOE ε4 in AD pathogenesis. The results of the multimodal analyses will provide new insights into underlying mechanisms and facilitate the discovery of new diagnostic and prognostic AD biomarkers. All researchers can apply for access to the EMIF-AD MBD data by submitting a research proposal via the EMIF-AD Catalog.

KEYWORDS:

Alzheimer’s disease; Biomarkers; Cerebrospinal fluid; DNA; Genomics; Magnetic resonance imaging; Metabolomics; Multimodal; Plasma; Proteomics

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