Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is affected by several genetic variants. It has been demonstrated that genetic variants affect brain organization and function. In this study, using whole genome-wide association studies (GWAS), we analyzed the functional magnetic resonance imaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative dataset (ADNI) dataset and identified genetic variants associated with the topology of the functional brain network http://www.adni-info.org. We found three novel loci (rs2409627, rs9647533, and rs11955845) in an intron of the phosphodiesterase 4D (PDE4D) gene that contribute to abnormalities in the topological organization of the functional network. In particular, compared to the wild-type genotype, the subjects carrying the PDE4D variants had altered network properties, including a significantly reduced clustering coefficient, small-worldness, global and local efficiency, a significantly enhanced path length and a normalized path length. In addition, we found that all global brain network attributes were affected by PDE4D variants to different extents as the disease progressed. Additionally, brain regions with alterations in nodal efficiency due to the variations in PDE4D were predominant in the limbic lobe, temporal lobe and frontal lobes. PDE4D has a great effect on memory consolidation and cognition through long-term potentiation (LTP) effects and/or the promotion of inflammatory effects. PDE4D variants might be a main reasons underlyling for the abnormal topological properties and cognitive impairment. Furthermore, we speculated that PDE4D is a risk factor for neural degenerative diseases and provided important clues for the earlier detection and therapeutic intervention for AD.

阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，受多种遗传变异影响。已经证明遗传变异会影响大脑的组织和功能。在这项研究中，我们使用全基因组关联研究（GWAS），分析了功能性磁共振成像和来自阿尔茨海默氏病神经影像主动性数据集（ADNI）的遗传数据，并确定了与功能性大脑网络拓扑相关的遗传变异http://www.adni-info.org。我们在磷酸二酯酶4D（PDE4D）基因的内含子中发现了三个新的基因座（rs2409627，rs9647533和rs11955845），这些基因可导致功能网络的拓扑结构异常。尤其是，与野生型基因型相比，携带PDE4D变体的受试者的网络特性发生了变化，包括显着降低的聚类系数，小世界性，全局和局部效率，显着增强的路径长度和标准化的路径长度。此外，我们发现随着疾病的进展，所有全球脑网络属性都受到PDE4D变异的不同程度的影响。此外，由于PDE4D的变化而导致节点效率发生改变的大脑区域主要分布在角膜缘，颞叶和额叶中。PDE4D通过长期增强（LTP）作用和/或促进炎症作用，对记忆巩固和认知有很大影响。PDE4D变异可能是造成异常拓扑特性和认知障碍的主要原因。此外，我们推测PDE4D是神经退行性疾病的危险因素，并为AD的早期发现和治疗干预提供了重要的线索。