INTRODUCTION Microstructural abnormalities in white matter (WM) are often reported in Alzheimer's disease (AD). However, it is unclear which brain regions have the strongest WM changes in presymptomatic AD and what biological processes underlie WM abnormality during disease progression. METHODS We developed a systems biology framework to integrate matched diffusion tensor imaging (DTI), genetic and transcriptomic data to investigate regional vulnerability to AD and identify genetic risk factors and gene subnetworks underlying WM abnormality in AD. RESULTS We quantified regional WM abnormality and identified most vulnerable brain regions. A SNP rs2203712 in CELF1 was most significantly associated with several DTI-derived features in the hippocampus, the top ranked brain region. An immune response gene subnetwork in the blood was most correlated with DTI features across all the brain regions. DISCUSSION Incorporation of image analysis with gene network analysis enhances our understanding of disease progression and facilitates identification of novel therapeutic strategies for AD.

中文翻译：

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阿尔茨海默病白质微结构异常的系统建模。


简介 白质 (WM) 的微观结构异常经常在阿尔茨海默病 (AD) 中出现。然而，目前尚不清楚哪些大脑区域在 AD 症状前具有最强的 WM 变化，以及疾病进展过程中哪些生物过程导致 WM 异常。方法 我们开发了一个系统生物学框架，整合匹配的扩散张量成像 (DTI)、遗传和转录组数据，以调查 AD 的区域易感性，并确定 AD 中 WM 异常的遗传风险因素和基因子网络。结果 我们量化了区域 WM 异常并确定了最脆弱的大脑区域。 CELF1 中的 SNP rs2203712 与海马体（排名最高的大脑区域）中的几个 DTI 衍生特征最显着相关。血液中的免疫反应基因子网络与所有大脑区域的 DTI 特征最相关。讨论 图像分析与基因网络分析的结合增强了我们对疾病进展的理解，并有助于识别 AD 的新治疗策略。