[en] Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aβ1-42.
Disciplines :
Neurology
Author, co-author :
Ramirez, Alfredo; Department of Psychiatry and Psychotherapy, Institute of Human Genetics, alfredo.ramirez@ukb.uni-bonn.de
van der Flier, Wiesje M; Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands
Herold, Christine; German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
Ramonet, David; Clinical Neuroscience Unit, Department of Neurology
Heilmann, Stefanie; Institute of Human Genetics, Department of Genomics, Life & Brain Center
Lewczuk, Piotr; Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
Popp, Julius; Department of Psychiatry and Psychotherapy
Lacour, André; German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
Drichel, Dmitriy; German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
Louwersheimer, Eva; Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands
Kummer, Markus P; Clinical Neuroscience Unit, Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
Cruchaga, Carlos; Department of Psychiatry, Hope Center for Neurological Disorders, School of Medicine
Hoffmann, Per; Institute of Human Genetics, Department of Genomics, Life & Brain Center, Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, CH-4058, Basel, Switzerland
Teunissen, Charlotte; Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands
Holstege, Henne; Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands
Kornhuber, Johannes; Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
Peters, Oliver; Department of Psychiatry, Charité, 14050, Berlin, Germany
Naj, Adam C; Center for Clinical Epidemiology & Biostatistics, University of Pennsylvania, PA 19104, Philadelphia, USA
Chouraki, Vincent; Department of Neurology, Boston University School of Medicine, MA 02118, Boston, USA, The Framingham Heart Study, MA 01702, Framingham, USA
Bellenguez, Céline; Inserm, U744, Lille 59000, France, Université Lille 2, Lille 59000, France, Institut Pasteur de Lille, Lille 59000, France
Gerrish, Amy; Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK
International Genomics of Alzheimer's Project (IGAP)
Heun, Reiner; Department of Psychiatry and Psychotherapy
Frölich, Lutz; Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany
Hüll, Michael; Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, 79106, Freiburg, Germany
Buscemi, Lara; Department of Fundamental Neurosciences, UNIL, 1005 Lausanne, Switzerland and
Herms, Stefan; Institute of Human Genetics, Department of Genomics, Life & Brain Center, Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, CH-4058, Basel, Switzerland
Kölsch, Heike; Department of Psychiatry and Psychotherapy
Scheltens, Philip; Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands
Breteler, Monique M; German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
Rüther, Eckart; Department of Psychiatry and Psychotherapy, University of Göttingen, 37075 Göttingen, Germany
Wiltfang, Jens; Department of Psychiatry and Psychotherapy, University of Göttingen, 37075 Göttingen, Germany
Goate, Alison; Department of Psychiatry, Department of Genetics, Washington University, St. Louis, MO 63110, USA
Jessen, Frank; Department of Psychiatry and Psychotherapy, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
Maier, Wolfgang; Department of Psychiatry and Psychotherapy, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
HENEKA, Michael ; Clinical Neuroscience Unit, Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
Becker, Tim; Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, 53127, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany
Nöthen, Markus M; Institute of Human Genetics, Department of Genomics, Life & Brain Center
This work was supported by grants from the Bundesministerium für Bildung und Forschung (BMBF) (KND grant 01 GI 0422 and KNDD grant 01GI 0711), as well as grants from the Deutsche Forschungsgemeinschaft (DFG) (BE 3828/3-2 and BE 3828/ 4-1 to T.B., HE 3350/8-2 (KFO177) to M.T.H.), T.B., M.T.H. and M.M.N. are members of the DFG cluster of excellence ImmunoSensation. This work was also supported by the Biomar-kAPD Project of the Joint Programme—Neurodegenerative Disease Research by a grant from the BMBF (01ED1203D to P.L. and M.T.H.). Research of the VUmc Alzheimer center is part of the neurodegeneration research program of the Neuroscience Campus Amsterdam, the Netherlands. The VUmc Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Data used in preparation of this article were obtained from the ADNI database (http://adni. loni.ucla.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec, Inc.; Bristol-Myers Squibb Company; Eisai, Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Inno-genetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer, Inc.; Piramal Imaging; Servier; Synarc, Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Co-operative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by National Institute of Health (grants numbers P30 AG010129 and K01 AG030514).
