Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults.
Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults.
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DOI：
10.1523/jneurosci.5794-10.2011
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发表时间：
2011-05-04
期刊：
影响因子：
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通讯作者：
Thompson PM
中科院分区：
文献类型：
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作者：
Braskie MN;Jahanshad N;Stein JL;Barysheva M;McMahon KL;de Zubicaray GI;Martin NG;Wright MJ;Ringman JM;Toga AW;Thompson PM
晚发性阿尔茨海默病（AD）有很强的遗传风险，但到目前为止，很少有基因变异被确定为可靠的风险。clusterin（CLU）基因变体rs11136000的一个新确认的遗传风险等位基因C由大约88%的高加索人携带。C等位基因比T等位基因导致晚发性AD的几率高1.16。AD患者局部白色物质完整性降低。我们评估了CLU风险变异是否与健康年轻人较低的白色完整性相似相关。早期大脑差异的证据将为症状发作前几十年的干预提供目标。我们用弥散张量成像（DTI）扫描了398名健康年轻人（平均年龄23.6 ± 2.2岁），这是一种对活体大脑中白色物质完整性敏感的磁共振成像（MRI）变体。我们使用混合模型回归评估了大脑中每个点的遗传关联，以绘制这些关联与白色物质完整性的轮廓。CLU变异体的每个C等位基因拷贝都与多个脑区中较低的各向异性分数（FA）相关，FA是一种被广泛接受的白色物质完整性测量方法，包括已知在AD中退化的几个脑区。这些区域包括胼胝体压部、穹窿、扣带回以及两侧大脑半球的上级和下纵束。年轻健康的CLU基因风险变异携带者表现出明显的低白色物质完整性，这可能会增加在以后生活中发展为AD的脆弱性。
There is a strong genetic risk for late-onset Alzheimer’s disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by approximately 88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether the CLU risk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset. We scanned 398 healthy young adults (mean age 23.6 ± 2.2 years) with diffusion tensor imaging (DTI), a variation of magnetic resonance imaging (MRI) sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed model regression at each point in the brain to map the profile of these associations with white matter integrity. Each C allele copy of the CLU variant was associated with lower fractional anisotropy (FA) - a widely accepted measure of white matter integrity- in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. Young healthy carriers of the CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life.