Su Fan, Shu Hao, Ye Qing, Xie Chunming, Yuan Baoyu, Zhang Zhijun, Bai Feng
Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
J Alzheimers Dis. 2017;56(2):491-507. doi: 10.3233/JAD-160787.
The aim of the study was to investigate the cognitive significance of the changes in default mode network (DMN) during the process of Alzheimer's disease (AD) and the genetic basis that drives the alteration. Eighty-seven subjects with mild cognitive impairment (MCI) and 131 healthy controls (HC) were employed at baseline, and they had the genetic risk scores (GRS) based on the GWAS-validated AD-related top loci. Eleven MCIs who converted to AD (c-MCIs), 32 subjects who remained stable (nc-MCIs), and 56 HCs participated in the follow-up analyses after an average of 35 months. Decreased functional connectivity (FC) within temporal cortex was identified for MCIs at baseline, which was partially determined by the GRS; moreover, compensations may occur within the frontal-parietal brain to maintain relatively intact cognition. During the follow-ups, c-MCIs exhibited more FC declines within the prefrontal-parietal lobes and parahippocampal gyrus/hippocampus than the HCs and nc-MCIs. The GRS did not significantly vary among the three groups, whereas associations were identified at risky alleles and FC declines in all AD spectra. Interestingly, the influence of APOEɛ4 varied as the disease progressed; APOEɛ4 was associated with longitudinal FC decreases only for HCs in the single variance-based analyses and deteriorated DMN integration in nc-MCIs by combining the effects of other loci. However, the GRS without APOEɛ4 predicted FC decline for converters. It is suggested that the integration of multilocus genetic risk predicted the longitudinal trajectory of DMN and may be used as a clinical strategy to track AD progression.
本研究的目的是调查阿尔茨海默病（AD）病程中默认模式网络（DMN）变化的认知意义以及驱动这种改变的遗传基础。研究纳入了87名轻度认知障碍（MCI）患者和131名健康对照（HC）作为基线研究对象，他们基于全基因组关联研究（GWAS）验证的AD相关顶级位点获得了遗传风险评分（GRS）。平均35个月后，11名转化为AD的MCI患者（c-MCI）、32名病情稳定的患者（nc-MCI）和56名HC参与了随访分析。在基线时，MCI患者颞叶皮质内的功能连接（FC）降低，这部分由GRS决定；此外，额顶叶脑区可能会出现代偿以维持相对完整的认知。在随访期间，c-MCI患者前额叶-顶叶叶和海马旁回/海马的FC下降比HC和nc-MCI患者更明显。三组之间的GRS没有显著差异，而在所有AD谱系中，风险等位基因与FC下降之间存在关联。有趣的是，APOEɛ4的影响随疾病进展而变化；在基于单变量的分析中，APOEɛ4仅与HC的纵向FC下降相关，并且通过结合其他位点的效应，在nc-MCI患者中使DMN整合恶化。然而，不包含APOEɛ4的GRS可预测转化者的FC下降。研究表明，多位点遗传风险的整合可预测DMN的纵向轨迹，并可作为追踪AD进展的临床策略。
