TY  - JOUR
AU  - Franzmeier, Nicolai
AU  - Ren, Jinyi
AU  - Damm, Alexander
AU  - Monté-Rubio, Gemma
AU  - Boada, Mercè
AU  - Ruiz, Agustín
AU  - Ramirez, Alfredo
AU  - Jessen, Frank
AU  - Düzel, Emrah
AU  - Rodríguez Gómez, Octavio
AU  - Benzinger, Tammie
AU  - Goate, Alison
AU  - Karch, Celeste M
AU  - Fagan, Anne M
AU  - McDade, Eric
AU  - Bürger, Katharina
AU  - Levin, Johannes
AU  - Duering, Marco
AU  - Dichgans, Martin
AU  - Suárez-Calvet, Marc
AU  - Haass, Christian
AU  - Gordon, Brian A
AU  - Lim, Yen Ying
AU  - Masters, Colin L
AU  - Janowitz, Daniel
AU  - Catak, Cihan
AU  - Wolfsgruber, Steffen
AU  - Wagner, Michael
AU  - Milz, Esther
AU  - Moreno-Grau, Sonia
AU  - Teipel, Stefan
AU  - Grothe, Michel J
AU  - Kilimann, Ingo
AU  - Rossor, Martin
AU  - Fox, Nick
AU  - Laske, Christoph
AU  - Chhatwal, Jasmeer
AU  - Falkai, Peter
AU  - Perneczky, Robert
AU  - Lee, Jae-Hong
AU  - Spottke, Annika
AU  - Boecker, Henning
AU  - Brosseron, Frederic
AU  - Fließbach, Klaus
AU  - Heneka, Michael T
AU  - Nestor, Peter
AU  - Peters, Oliver
AU  - Fuentes Casan, Manuel
AU  - Menne, Felix
AU  - Priller, Josef
AU  - Spruth, Eike J
AU  - Franke, Christiana
AU  - Schneider, Anja
AU  - Westerteicher, Christine
AU  - Speck, Oliver
AU  - Wiltfang, Jens
AU  - Bartels, Claudia
AU  - Araque Caballero, Miguel Ángel
AU  - Metzger, Coraline
AU  - Bittner, Daniel
AU  - Salloway, Stephen
AU  - Danek, Adrian
AU  - Hassenstab, Jason
AU  - Yakushev, Igor
AU  - Schofield, Peter R
AU  - Morris, John C
AU  - Bateman, Randall J
AU  - Ewers, Michael
TI  - The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease.
JO  - Molecular psychiatry
VL  - 26
IS  - 2
SN  - 1359-4184
CY  - London
PB  - Macmillan
M1  - DZNE-2020-07405
SP  - 614-628
PY  - 2021
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30899092
C2  - pmc:PMC6754794
DO  - DOI:10.1038/s41380-019-0404-6
UR  - https://pub.dzne.de/record/141083
ER  -