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Front Aging Neurosci. 2018 Dec 11;10:409. doi: 10.3389/fnagi.2018.00409. eCollection 2018.

Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result.

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Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kigndom.
Biomedical Research Unit for Dementia, NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust, London, United Kingdom.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
MRC Biostatistics Unit, Cambridge Biomedical Campus, Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.
Proteomics Facility, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
GE Healthcare Life Sciences Core Imaging, London, United Kingdom.
Biosciences, GE Global Research, Niskayuna, NY, United States.
GE Healthcare Life Sciences Core Imaging, Marlborough, MA, United States.
Neurodegenerative Diseases Unit, Centro Dino Ferrari, University of Milan, Milan, Italy.
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Center for Memory Disorders and Laboratory of Clinical Neurochemistry, Neurology Clinic, University of Perugia, Perugia, Italy.
Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Janssen Neuroscience Research & Development, Titusville, NJ, United States.
Department of Neurology, Alzheimer Centre, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands.
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands.
Department of Clinical Chemistry, Neurochemistry Lab and Biobank, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.


Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/Aβ42 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ42 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/Aβ42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/Aβ42. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aβ42 (P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ42 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.


Alzheimer’s disease; amyloid; biomarkers; blood; ficolin-2; plasma; proteomics; tau

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