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Mol Psychiatry. 2019 Mar 21. doi: 10.1038/s41380-019-0404-6. [Epub ahead of print]

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

Author information

1
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.
2
Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain.
3
CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.
4
Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany.
5
Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany.
6
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
7
German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
8
Department of Radiology, Washington University in St Louis, St Louis, MO, USA.
9
Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
10
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11
Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
12
Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA.
13
Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
14
Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
15
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
16
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
17
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
18
Barcelonabeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Catalonia, Spain.
19
Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
20
Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USA.
21
Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, USA.
22
The Florey Institute, The University of Melbourne, Parkville, VIC, Australia.
23
German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
24
Department of Psychosomatic Medicine, University Hospital Rostock, Rostock, Germany.
25
Dementia Research Centre, University College London, Queen Square, London, UK.
26
Hertie Institute for Clinical Brain Research, Tübingen, Germany.
27
Germany and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
28
Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
29
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany.
30
Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science, Technology and Medicine, London, UK.
31
Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
32
Department of Neurology, University of Bonn, Bonn, Germany.
33
Department of Radiology, University of Bonn, Bonn, Germany.
34
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
35
German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
36
Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany.
37
Department of Neuropsychiatry, Charité, Berlin, Germany.
38
Leibniz Institute for Neurobiology, Magdeburg, Germany.
39
Center for Behavioral Brain Sciences, Magdeburg, Germany.
40
Department for Biomedical Magnetic Resonance, Institute for Physics, Otto-von-Guericke University, Magdeburg, Germany.
41
German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany.
42
Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany.
43
iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal.
44
Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
45
Department of Nuclear Medicine, Technical University of Munich, Munich, Germany.
46
Neuroscience Research Australia, Barker Street Randwick, Sydney, NSW, 2031, Australia.
47
School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
48
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany. michael.ewers@med.uni-muenchen.de.

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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