The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease
The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease
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DOI：
10.1038/s41380-019-0404-6
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发表时间：
2021-02-01
影响因子：
11
通讯作者：
Ewers, Michael
中科院分区：
文献类型：
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作者：
Franzmeier, Nicolai;Ren, Jinyi;Ewers, Michael
在阿尔茨海默病（AD）中，编码脑源性神经营养因子（BDNFVal66Met）基因的单核苷酸多态性与原发性AD病理（β -淀粉样蛋白，a β）对神经变性和认知能力下降的影响更严重相关，使BDNFVal66Met成为AD认知功能障碍的重要调节因子。然而，BDNFVal66Met对AD认知障碍背后的功能网络的影响尚不清楚。采用交叉验证方法，我们首先探索了来自显性遗传阿尔茨海默病网络（DIAN）的常染色体显性阿尔茨海默病（ADAD）受试者中BDNFVal66Met对静息状态fMRI评估的功能网络的影响。在对6个主要大型网络的基于种子的连通性分析中，我们发现，与BDNFVal同型同源细胞相比，BDNFVal66Met载体的海马（种子）到内侧额叶的连通性下降更强。BDNFVal66Met与任何其他网络的连通性无关。接下来，我们测试了BDNFVal66Met海马-内侧额叶连通性更明显的下降是否也可以在偶发A β的老年受试者中发现，包括主观认知能力下降组（N = 149， FACEHBI研究）和临床前至AD痴呆组（N = 114， DELCODE研究）。在这两个独立招募的组中，BDNFVal66Met与a β水平异常（通过生物体液测定或淀粉样蛋白pet评估）对海马-内侧-额叶连通性降低的更强影响相关，海马体积和其他混杂因素得到控制。在DIAN和DELCODE研究中，较低的海马-内侧额叶连通性与较低的整体认知表现有关。这些结果表明，BDNFVal66Met选择性地与海马体-额叶连接对原发性AD病理的更高易感性相关，从而导致更大的AD相关认知障碍。
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, A beta) 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 A beta, 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 A beta-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.