The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Franzmeier Nicolai, Ren Jinyi, Damm Alexander, Monté-Rubio Gemma, Boada Mercè, Ruiz Agustín, Ramirez Alfredo, Jessen Frank, Düzel Emrah, Rodríguez Gómez Octavio, Benzinger Tammie, Goate Alison, Karch Celeste M, Fagan Anne M, McDade Eric, Buerger Katharina, Levin Johannes, Duering Marco, Dichgans Martin, Suárez-Calvet Marc, Haass Christian, Gordon Brian A, Lim Yen Ying, Masters Colin L, Janowitz Daniel, Catak Cihan, Wolfsgruber Steffen, Wagner Michael, Milz Esther, Moreno-Grau Sonia, Teipel Stefan, Grothe Michel J, Kilimann Ingo, Rossor Martin, Fox Nick, Laske Christoph, Chhatwal Jasmeer, Falkai Peter, Perneczky Robert, Lee Jae-Hong, Spottke Annika, Boecker Henning, Brosseron Frederic, Fliessbach Klaus, Heneka Michael T, Nestor Peter, Peters Oliver, Fuentes Manuel, Menne Felix, Priller Josef, Spruth Eike J, Franke Christiana, Schneider Anja, Westerteicher Christine, Speck Oliver, Wiltfang Jens, Bartels Claudia, Araque Caballero Miguel Ángel, Metzger Coraline, Bittner Daniel, Salloway Stephen, Danek Adrian, Hassenstab Jason, Yakushev Igor, Schofield Peter R, Morris John C, Bateman Randall J, Ewers Michael
Аннотация
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.