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Single Nucleotide Polymorphisms in Alzheimer’s Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age
Journal of Alzheimer’s Disease ( IF 4 ) Pub Date : 2020-09-20 , DOI: 10.3233/jad-200444
Jenna Katherine Blujus 1 , Laura Elizabeth Korthauer 1, 2 , Elizabeth Awe 1, 3 , Marijam Frahmand 1 , Ira Driscoll 1
Affiliation  

Background:It is critical to identify individuals at risk for Alzheimer’s disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE, CLU, CR1, PICALM, and SORL1 that confer increased risk of AD. Objective:In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal control network (FPN), and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 –60; N = 123; 74 females). Methods:Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Results:Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (ps < 0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (ps < 0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p < 0.05). There were no APOE- or PICALM-related differences in any of the networks investigated (ps > 0.05). Conclusion:This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU, CR1, and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD.

中文翻译:

阿尔茨海默病风险基因中的单核苷酸多态性与中年人的内在连通性有关

背景:在疾病时间过程的早期,例如中年,最好在临床症状出现之前识别有患阿尔茨海默病 (AD) 风险的个体至关重要,此时干预工作可能会更成功。全基因组关联和候选基因研究已经确定了 APOE、CLU、CR1、PICALM 和 SORL1 中的单核苷酸多态性 (SNP),它们会增加 AD 的风险。目的:在目前的研究中,我们调查了这些基因中的 S​​NP 与健康、非正常人群中默认模式网络 (DMN)、额顶控制网络 (FPN) 和执行控制网络 (ECN) 内静息状态功能连接之间的关联。痴呆的中年人(40-60 岁;N = 123;74 名女性)。方法:使用模板匹配程序通过独立成分分析确定感兴趣的静息状态网络,并使用对偶回归提取个体空间图和时间课程。结果:在后部 DMN 中,功能连接与 CR1 rs1408077 和 CLU rs9331888 多态性相关(ps < 0.05)。FPN 连接与 CR1 rs1408077、CLU rs1136000、SORL1 rs641120 和 SORL1 rs689021 (ps < 0.05) 相关联。ECN 内的功能连接与 CLU rs11136000 相关(p < 0.05)。在所调查的任何网络中都没有与 APOE 或 PICALM 相关的差异(ps > 0.05)。结论:这是首次证明了健康中年人CLU、CR1和SORL1内在网络连接与AD风险等位基因之间的关系。
更新日期:2020-09-23
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