Article | Published:

The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

Molecular Psychiatry (2019) | Download Citation

Abstract

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.

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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.

Author information

Affiliations

  1. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany

    • Nicolai Franzmeier
    • , Jinyi Ren
    • , Alexander Damm
    • , Katharina Buerger
    • , Marco Duering
    • , Martin Dichgans
    • , Daniel Janowitz
    • , Cihan Catak
    • , Miguel Ángel Araque Caballero
    •  & Michael Ewers
  2. Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain

    • Gemma Monté-Rubio
    • , Mercè Boada
    • , Agustín Ruiz
    • , Octavio Rodríguez Gómez
    •  & Sonia Moreno-Grau
  3. CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain

    • Mercè Boada
    • , Agustín Ruiz
    • , Octavio Rodríguez Gómez
    •  & Sonia Moreno-Grau
  4. Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany

    • Alfredo Ramirez
    • , Frank Jessen
    •  & Esther Milz
  5. Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany

    • Alfredo Ramirez
    • , Steffen Wolfsgruber
    • , Michael Wagner
    • , Frederic Brosseron
    • , Klaus Fliessbach
    • , Michael T. Heneka
    • , Anja Schneider
    •  & Christine Westerteicher
  6. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    • Frank Jessen
    • , Steffen Wolfsgruber
    • , Michael Wagner
    • , Annika Spottke
    • , Henning Boecker
    • , Frederic Brosseron
    • , Klaus Fliessbach
    • , Michael T. Heneka
    • , Anja Schneider
    •  & Christine Westerteicher
  7. German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany

    • Emrah Düzel
    • , Peter Nestor
    • , Oliver Speck
    • , Coraline Metzger
    •  & Daniel Bittner
  8. Department of Radiology, Washington University in St Louis, St Louis, MO, USA

    • Tammie Benzinger
  9. Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA

    • Tammie Benzinger
    • , Celeste M. Karch
    • , Anne M. Fagan
    • , Brian A. Gordon
    • , John C. Morris
    •  & Randall J. Bateman
  10. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Alison Goate
  11. Ronald M. Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Alison Goate
  12. Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA

    • Celeste M. Karch
    •  & Anne M. Fagan
  13. Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA

    • Celeste M. Karch
    •  & John C. Morris
  14. Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA

    • Anne M. Fagan
    • , Eric McDade
    • , Jason Hassenstab
    • , John C. Morris
    •  & Randall J. Bateman
  15. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    • Katharina Buerger
    • , Johannes Levin
    • , Martin Dichgans
    • , Marc Suárez-Calvet
    • , Christian Haass
    • , Robert Perneczky
    •  & Miguel Ángel Araque Caballero
  16. Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany

    • Johannes Levin
    •  & Adrian Danek
  17. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    • Martin Dichgans
    •  & Robert Perneczky
  18. Barcelonabeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Catalonia, Spain

    • Marc Suárez-Calvet
  19. Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

    • Marc Suárez-Calvet
    •  & Christian Haass
  20. Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USA

    • Brian A. Gordon
  21. Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, USA

    • Brian A. Gordon
  22. The Florey Institute, The University of Melbourne, Parkville, VIC, Australia

    • Yen Ying Lim
    •  & Colin L. Masters
  23. German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany

    • Stefan Teipel
    • , Michel J Grothe
    •  & Ingo Kilimann
  24. Department of Psychosomatic Medicine, University Hospital Rostock, Rostock, Germany

    • Stefan Teipel
  25. Dementia Research Centre, University College London, Queen Square, London, UK

    • Martin Rossor
    •  & Nick Fox
  26. Hertie Institute for Clinical Brain Research, Tübingen, Germany

    • Christoph Laske
  27. Germany and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany

    • Christoph Laske
  28. Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA

    • Jasmeer Chhatwal
  29. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany

    • Peter Falkai
    •  & Robert Perneczky
  30. Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science, Technology and Medicine, London, UK

    • Robert Perneczky
  31. Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

    • Jae-Hong Lee
  32. Department of Neurology, University of Bonn, Bonn, Germany

    • Annika Spottke
  33. Department of Radiology, University of Bonn, Bonn, Germany

    • Henning Boecker
  34. Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia

    • Peter Nestor
  35. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany

    • Oliver Peters
    • , Manuel Fuentes
    • , Felix Menne
    • , Josef Priller
    • , Eike J. Spruth
    •  & Christiana Franke
  36. Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany

    • Oliver Peters
    • , Manuel Fuentes
    •  & Felix Menne
  37. Department of Neuropsychiatry, Charité, Berlin, Germany

    • Josef Priller
    • , Eike J. Spruth
    •  & Christiana Franke
  38. Leibniz Institute for Neurobiology, Magdeburg, Germany

    • Oliver Speck
  39. Center for Behavioral Brain Sciences, Magdeburg, Germany

    • Oliver Speck
  40. Department for Biomedical Magnetic Resonance, Institute for Physics, Otto-von-Guericke University, Magdeburg, Germany

    • Oliver Speck
  41. German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany

    • Jens Wiltfang
  42. Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany

    • Jens Wiltfang
    •  & Claudia Bartels
  43. iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal

    • Jens Wiltfang
  44. Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA

    • Stephen Salloway
  45. Department of Nuclear Medicine, Technical University of Munich, Munich, Germany

    • Igor Yakushev
  46. Neuroscience Research Australia, Barker Street Randwick, Sydney, NSW, 2031, Australia

    • Peter R. Schofield
  47. School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    • Peter R. Schofield

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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.

Corresponding author

Correspondence to Michael Ewers.

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DOI

https://doi.org/10.1038/s41380-019-0404-6