[en] [en] OBJECTIVE: Decreased amyloid beta (Aβ) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer's disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages.
METHODS: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification.
RESULTS: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of Aβ42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations.
INTERPRETATION: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.
Disciplines :
Neurology
Author, co-author :
Bergström, Sofia ; Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
Remnestål, Julia ; Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
Yousef, Jamil ; Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
Olofsson, Jennie ; Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
Markaki, Ioanna ; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
Carvalho, Stephanie; Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Assistance-Publique Hôpitaux de Paris, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Department of Neurology, Centre d'Investigation Clinique Neurosciences, Paris, France
Corvol, Jean-Christophe ; Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Assistance-Publique Hôpitaux de Paris, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Department of Neurology, Centre d'Investigation Clinique Neurosciences, Paris, France
Kultima, Kim ; Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Kilander, Lena; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden
Löwenmark, Malin; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden
Ingelsson, Martin ; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden
Blennow, Kaj ; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg ; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Zetterberg, Henrik ; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg ; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden ; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK ; UK Dementia Research Institute at UCL, London, UK
Nellgård, Bengt ; Anesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, Mölndal, Sweden ; Department of Anesthesiology and Intensive Care Medicine, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg
Brosseron, Frederic ; Universitätsklinikum Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Bosch, Beatriz ; Alzheimer's and other cognitive disorders Unit. Service of Neurology, Hospital Clínic de Barcelona, Institut d'Investigació Biomèdica August Pi i Sunyer, University of Barcelona, Barcelona, Spain
Sanchez-Valle, Raquel ; Alzheimer's and other cognitive disorders Unit. Service of Neurology, Hospital Clínic de Barcelona, Institut d'Investigació Biomèdica August Pi i Sunyer, University of Barcelona, Barcelona, Spain
Månberg, Anna ; Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
Svenningsson, Per ; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
Nilsson, Peter ; Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (AETIONOMY, grant n. 115568) including in‐kind contributions from the EFPIA members involved. The work was also funded by KTH Center for Applied Precision Medicine (KCAP), the Erling‐Persson Family Foundation, Demensfonden, and Stockholm Brain Institute. 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), AD Strategic Fund and the Alzheimer's Association (#ADSF‐21‐831376‐C, #ADSF‐21‐831381‐C and #ADSF‐21‐831377‐C), the Olav Thon Foundation, the Erling‐Persson Family Foundation, Hjärnfonden, Sweden (#FO2019‐0228), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017‐00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB‐201809‐2016615), the Swedish Alzheimer Foundation (#AF‐742881), Hjärnfonden, Sweden (#FO2017‐0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‐agreement (#ALFGBG‐715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236). KK is supported by The Gun and Bertil Stohne’s foundation, Geriatriska fonden, and Stiftelsen för Gamla Tjänarinnor.KB has served as a consultant or at advisory boards for Abcam, Axon, Biogen, Lilly, MagQu, Novartis, and Roche Diagnostics, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). J.C.C. has served in advisory boards for Air Liquide, Biogen, Denali, Ever Pharma, Idorsia, Prevail Therapeutic, Theranexus, UCB; and received grants from Sanofi and the Michael J Fox Foundation. The other authors declare that they have no competing interest.
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