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

Autor: Nick C. Fox, Claudia Bartels, Henning Boecker, Peter R. Schofield, Stefan J. Teipel, Josef Priller, Peter Falkai, Michael Ewers, Michael T. Heneka, Stephen Salloway, Coraline D. Metzger, Jae-Hong Lee, Alfredo Ramirez, Michel J. Grothe, Anja Schneider, Colin L. Masters, Nicolai Franzmeier, Igor Yakushev, Oliver Peters, Eric McDade, Johannes Levin, Christoph Laske, Daniel Bittner, Agustín Ruiz, Michael Wagner, Gemma Monté-Rubio, Sonia Moreno-Grau, Miguel Ángel Araque Caballero, Felix Menne, Jason Hassenstab, Yen Ying Lim, Jens Wiltfang, Christian Haass, Anne M. Fagan, Frank Jessen, Marc Suárez-Calvet, Eike Jakob Spruth, Alison Goate, Adrian Danek, Manuel Fuentes, Octavio Rodríguez Gómez, Esther Milz, Christiana Franke, Brian A. Gordon, Robert Perneczky, Martin Dichgans, Martin N. Rossor, Klaus Fliessbach, Marco Duering, Tammie L.S. Benzinger, Celeste M. Karch, Peter J. Nestor, Frederic Brosseron, Jasmeer P. Chhatwal, Cihan Catak, Christine Westerteicher, Daniel Janowitz, Ingo Kilimann, Oliver Speck, Jinyi Ren, Katharina Buerger, Randall J. Bateman, Mercè Boada, Alexander Damm, Steffen Wolfsgruber, John C. Morris, Annika Spottke, Emrah Düzel
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Molecular psychiatry
Molecular psychiatry 26(2), 614-628 (2021). doi:10.1038/s41380-019-0404-6
Franzmeier, N, Ren, J, Damm, A, Monté-rubio, G, Boada, M, Ruiz, A, Ramirez, A, Jessen, F, Düzel, E, Rodríguez Gómez, O, Benzinger, T, Goate, A, Karch, C M, Fagan, A M, Mcdade, E, Buerger, K, Levin, J, Duering, M, Dichgans, M, Suárez-calvet, M, Haass, C, Gordon, B A, Lim, Y Y, Masters, C L, Janowitz, D, Catak, C, Wolfsgruber, S, Wagner, M, Milz, E, Moreno-grau, S, Teipel, S, Grothe, M J, Kilimann, I, Rossor, M, Fox, N, Laske, C, Chhatwal, J, Falkai, P, Perneczky, R, Lee, J, Spottke, A, Boecker, H, Brosseron, F, Fliessbach, K, Heneka, M T, Nestor, P, Peters, O, Fuentes, M, Menne, F, Priller, J, Spruth, E J, Franke, C, Schneider, A, Westerteicher, C, Speck, O, Wiltfang, J, Bartels, C, Araque Caballero, M Á, Metzger, C, Bittner, D, Salloway, S, Danek, A, Hassenstab, J, Yakushev, I, Schofield, P R, Morris, J C, Bateman, R J & Ewers, M 2019, ' The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease ', Molecular Psychiatry . https://doi.org/10.1038/s41380-019-0404-6
ISSN: 1476-5578
1359-4184
Popis: 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.
Databáze: OpenAIRE
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