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

Nicolai Franzmeier, Jinyi Ren, Alexander Damm, Gemma Monté-Rubio, Mercè Boada, Agustín Ruiz, Alfredo Ramirez, Frank Jessen, Emrah Düzel, Octavio Rodríguez Gómez, Tammie Benzinger, Alison Goate, Celeste M. Karch, Anne M. Fagan, Eric McDade, Katharina Buerger, Johannes Levin, Marco Duering, Martin Dichgans, Marc Suárez-CalvetChristian Haass, Brian A. Gordon, Yen Ying Lim, Colin L. Masters, Daniel Janowitz, Cihan Catak, Steffen Wolfsgruber, Michael Wagner, Esther Milz, Sonia Moreno-Grau, Stefan Teipel, Michel J. Grothe, Ingo Kilimann, Martin Rossor, Nick Fox, Christoph Laske, Jasmeer Chhatwal, Peter Falkai, Robert Perneczky, Jae Hong Lee, Annika Spottke, Henning Boecker, Frederic Brosseron, Klaus Fliessbach, Michael T. Heneka, Peter Nestor, Oliver Peters, Manuel Fuentes, Felix Menne, Josef Priller, Eike J. Spruth, Christiana Franke, Anja Schneider, Christine Westerteicher, Oliver Speck, Jens Wiltfang, Claudia Bartels, Miguel Ángel Araque Caballero, Coraline Metzger, Daniel Bittner, Stephen Salloway, Adrian Danek, Jason Hassenstab, Igor Yakushev, Peter R. Schofield, John C. Morris, Randall J. Bateman, Michael Ewers

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51 Scopus citations


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.

Original languageEnglish
Pages (from-to)614-628
Number of pages15
JournalMolecular Psychiatry
Issue number2
StatePublished - Feb 2021


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