Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA; Warren Alpert Medical School, Brown University, Providence, RI, USA.
Engineering and Technology Department, University of Wisconsin-Stout, Menomonie, WI, USA; Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
Neuroimage. 2018 Sep;178:295-305. doi: 10.1016/j.neuroimage.2018.05.052. Epub 2018 May 24.
The apolipoprotein E (APOE) ε4 allele is the best characterized genetic risk factor for Alzheimer's disease to date. Older APOE ε4 carriers (aged 60 + years) are known to have disrupted structural and functional connectivity, but less is known about APOE-associated network integrity in middle age. The goal of this study was to characterize APOE-related differences in network topology in middle age, as disentangling the early effects of healthy versus pathological aging may aid early detection of Alzheimer's disease and inform treatments. We performed resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) in healthy, cognitively normal, middle-aged adults (age 40-60; N = 76, 38 APOE ε4 carriers). Graph theoretical analysis was used to calculate local and global efficiency of 1) a whole brain rs-fMRI network; 2) a whole brain DTI network; and 3) the resting state structural connectome (rsSC), an integrated functional-structural network derived using functional-by-structural hierarchical (FSH) mapping. Our results indicated no APOE ε4-associated differences in network topology of the rs-fMRI or DTI networks alone. However, ε4 carriers had significantly lower global and local efficiency of the integrated rsSC compared to non-carriers. Furthermore, ε4 carriers were less resilient to targeted node failure of the rsSC, which mimics the neuropathological process of Alzheimer's disease. Collectively, these findings suggest that integrating multiple neuroimaging modalities and employing graph theoretical analysis may reveal network-level vulnerabilities that may serve as biomarkers of age-related cognitive decline in middle age, decades before the onset of overt cognitive impairment.
载脂蛋白 E (APOE) ε4 等位基因是迄今为止阿尔茨海默病最具特征的遗传风险因素。已知较年长的 APOE ε4 携带者（年龄在 60 岁及以上）存在结构和功能连接中断，但对于中年 APOE 相关网络完整性知之甚少。本研究的目的是描述中年时与 APOE 相关的网络拓扑结构差异，因为厘清健康衰老与病理性衰老的早期影响可能有助于阿尔茨海默病的早期检测，并为治疗提供信息。我们对健康、认知正常的中年成年人（年龄 40-60 岁；N=76，38 名 APOE ε4 携带者）进行了静息状态功能磁共振成像（rs-fMRI）和弥散张量成像（DTI）。使用图论分析计算了 1）全脑 rs-fMRI 网络；2）全脑 DTI 网络；3）静息状态结构连接组（rsSC）的局部和全局效率，rsSC 是使用功能-结构层次（FSH）映射得出的一个集成功能-结构网络。我们的结果表明，APOE ε4 与 rs-fMRI 或 DTI 网络的拓扑结构没有关联。然而，与非携带者相比，ε4 携带者的 rsSC 整体和局部效率明显较低。此外，与非携带者相比，ε4 携带者的 rsSC 对目标节点故障的弹性较低，这模拟了阿尔茨海默病的神经病理学过程。总之，这些发现表明，整合多种神经影像学模态并采用图论分析可能会揭示网络层面的脆弱性，这些脆弱性可能成为中年时与年龄相关认知能力下降的生物标志物，比明显认知障碍的发病早几十年。
