The Association between a Polygenic Alzheimer Score and Cortical Thickness in Clinically Normal Subjects
The Association between a Polygenic Alzheimer Score and Cortical Thickness in Clinically Normal Subjects
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DOI：
10.1093/cercor/bhr348
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发表时间：
2012-11-01
期刊：
影响因子：
3.7
通讯作者：
Sperling, Reisa A.
中科院分区：
文献类型：
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作者：
Sabuncu, Mert R.;Buckner, Randy L.;Sperling, Reisa A.
晚发性阿尔茨海默病（AD）有50-70%的遗传性，具有复杂的遗传基础。除了载脂蛋白E（APOE）β 4，主要的遗传风险因素，最近的全基因组关联研究（GWAS）已经确定了越来越多的序列变异与疾病相关。基于先前的大规模AD GWAS，我们使用最近开发的分析方法来计算多基因评分，该评分涉及多达26个独立的共同序列变体，并且与AD痴呆相关，高于APOE。然后，我们检查了临床正常（CN）人类受试者（N = 104）的多基因评分和磁共振成像衍生的AD易感皮质厚度测量值之间的相关性。AD特异性皮质厚度与多基因风险评分相关，即使在控制APOE基因型和脑脊液（CSF）β淀粉样蛋白（A β（1-42））水平后。此外，在CSF A β（1-42）水平在正常范围内的CN受试者和APOE β 3纯合子中，这种相关性仍然显著。观察到遗传风险变异与CN老年个体中AD易感区域的厚度相关，这表明多基因风险特征、神经影像学和CSF生物标志物的组合可能具有协同作用，有助于预测未来的认知能力下降。
Late-onset Alzheimer's disease (AD) is 50-70% heritable with complex genetic underpinnings. In addition to Apoliprotein E (APOE) epsilon 4, the major genetic risk factor, recent genome-wide association studies (GWAS) have identified a growing list of sequence variations associated with the disease. Building on a prior large-scale AD GWAS, we used a recently developed analytic method to compute a polygenic score that involves up to 26 independent common sequence variants and is associated with AD dementia, above and beyond APOE. We then examined the associations between the polygenic score and the magnetic resonance imaging-derived thickness measurements across AD-vulnerable cortex in clinically normal (CN) human subjects (N = 104). AD-specific cortical thickness was correlated with the polygenic risk score, even after controlling for APOE genotype and cerebrospinal fluid (CSF) levels of beta-amyloid (A beta(1-42)). Furthermore, the association remained significant in CN subjects with levels of CSF A beta(1-42) in the normal range and in APOE epsilon 3 homozygotes. The observation that genetic risk variants are associated with thickness across AD-vulnerable regions of interest in CN older individuals, suggests that the combination of polygenic risk profile, neuroimaging, and CSF biomarkers may hold synergistic potential to aid in the prediction of future cognitive decline.