Amyloid beta-Peptides; Brain-Derived Neurotrophic Factor; Aged; Amyloid beta-Peptides/metabolism; Brain/metabolism; Brain-Derived Neurotrophic Factor/genetics; Hippocampus/metabolism; Humans; Magnetic Resonance Imaging; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Alzheimer Disease/genetics; Cognitive Dysfunction; Alzheimer Disease; Brain; Hippocampus; Molecular Biology; Cellular and Molecular Neuroscience; Psychiatry and Mental Health
Abstract :
[en] In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.
Disciplines :
Neurology
Author, co-author :
Franzmeier, Nicolai ; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Ren, Jinyi; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Damm, Alexander; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Monté-Rubio, Gemma; Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain
Boada, Mercè; Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain ; CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain
Ruiz, Agustín; Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain ; CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain
Ramirez, Alfredo ; Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany
Jessen, Frank; Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Düzel, Emrah; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Rodríguez Gómez, Octavio; Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain ; CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain
Benzinger, Tammie; Department of Radiology, Washington University in St Louis, St Louis, MO, USA ; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA
Goate, Alison ; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA ; Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Karch, Celeste M ; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA ; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA ; Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA
Fagan, Anne M; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA ; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA ; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA
McDade, Eric; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA
Buerger, Katharina; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Levin, Johannes; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
Duering, Marco; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Dichgans, Martin; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Suárez-Calvet, Marc; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ; Barcelonabeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Catalonia, Spain ; Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
Haass, Christian ; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ; Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
Gordon, Brian A ; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA ; Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USA ; Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, USA
Lim, Yen Ying; The Florey Institute, The University of Melbourne, Parkville, VIC, Australia
Masters, Colin L; The Florey Institute, The University of Melbourne, Parkville, VIC, Australia
Janowitz, Daniel; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Catak, Cihan; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Wolfsgruber, Steffen; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Wagner, Michael; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Milz, Esther; Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany
Moreno-Grau, Sonia; Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain ; CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain
Teipel, Stefan; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic Medicine, University Hospital Rostock, Rostock, Germany
Grothe, Michel J ; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
Kilimann, Ingo; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
Rossor, Martin; Dementia Research Centre, University College London, Queen Square, London, UK
Fox, Nick; Dementia Research Centre, University College London, Queen Square, London, UK
Laske, Christoph; Hertie Institute for Clinical Brain Research, Tübingen, Germany ; Germany and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Chhatwal, Jasmeer; Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA
Falkai, Peter; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany
Perneczky, Robert ; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany ; Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science, Technology and Medicine, London, UK
Lee, Jae-Hong; Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
Spottke, Annika; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Neurology, University of Bonn, Bonn, Germany
Boecker, Henning; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Radiology, University of Bonn, Bonn, Germany
Brosseron, Frederic; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Fliessbach, Klaus; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
HENEKA, Michael ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Nestor, Peter; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany ; Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
Peters, Oliver; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany
Fuentes, Manuel; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany
Menne, Felix; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany
Priller, Josef; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Neuropsychiatry, Charité, Berlin, Germany
Spruth, Eike J; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Neuropsychiatry, Charité, Berlin, Germany
Franke, Christiana; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Neuropsychiatry, Charité, Berlin, Germany
Schneider, Anja; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Westerteicher, Christine; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Speck, Oliver; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany ; Leibniz Institute for Neurobiology, Magdeburg, Germany ; Center for Behavioral Brain Sciences, Magdeburg, Germany ; Department for Biomedical Magnetic Resonance, Institute for Physics, Otto-von-Guericke University, Magdeburg, Germany
Wiltfang, Jens ; German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany ; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany ; iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal
Bartels, Claudia; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany
Araque Caballero, Miguel Ángel; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Metzger, Coraline; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Bittner, Daniel; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Salloway, Stephen ; Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA
Danek, Adrian ; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
Hassenstab, Jason; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA
Yakushev, Igor; Department of Nuclear Medicine, Technical University of Munich, Munich, Germany
Schofield, Peter R ; Neuroscience Research Australia, Barker Street Randwick, Sydney, NSW, 2031, Australia ; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
Morris, John C; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA ; Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA ; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA
Bateman, Randall J; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA ; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA
Ewers, Michael; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany. michael.ewers@med.uni-muenchen.de
The FACEHBI study is supported by Grifols®, Piramal®, Araclon Biotech®, Laboratorios Echevarne S.A. and Fundació ACE, Institut Català de Neurociències Aplicades.
Funding text :
Funding This project was supported by The Dominantly Inherited Alzheimer’s Network (DIAN, UF1 AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), the NIHR Queen Square Dementia Biomedical Research Centre and the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1), and AMED under grant number JP17dk0207036 and JP17kk0205009. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. The FACEHBI study is supported by Grifols®, Piramal®, Araclon Biotech®, Laboratorios Echevarne S.A. and Fundació ACE, Institut Català de Neurociències Aplicades. M.E.—Alzheimer Forschung Initiative & LMU excellent; J.C.—K23AG049087; B.A.G.—K01AG053474, Barnes-Jewish Hospital Foundation Willman Scholar Fund; Y.Y.L.— National Health and Medical Research Council (NHMRC) GNT1111603, GNT1147465.Conflict of interest A.M.F. has received research funding from Biogen, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche, Genentech, and AbbVie and also consults for Araclon/Griffols and DiamiR.: Y.Y.L. has served as a scientific consultant to Biogen and Lundbeck; M.B. who has consulted or advisory board for Araclon, Grifols, Lilly, Nutricia, Roche and Servier. She received fees for lectures and funds for research from Araclon, Grifols, Nutricia, Roche and Servier. She has not received personal compensations from these organizations. A. Ruiz has consulted for Grifols and Landsteiner Genmed. He received funds for research and/or reimbursement of expenses for congresses attendance from Araclon, and Grifols. He has not received personal compensations from these organizations: T.B., Investigator, initiated research funding sponsored by Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) and Foundation for the NIH. Clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Roche, Jaansen, Biogen, and NIH. Travel sponsored by the American Society for Neuroradiology, Alzheimer’s Association International Convention, NIH. The remaining authors declare that they have no conflict of interest.
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