Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston.
JAMA Neurol. 2013 Sep 1;70(9):1150-7. doi: 10.1001/jamaneurol.2013.2815.
While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques.
To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait.
DESIGN, SETTING, AND PARTICIPANTS: Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers.
A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir.
Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition.
These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.
虽然已经确定了许多与临床阿尔茨海默病（AD）相关的遗传易感性基因座，但重要的是要确定这些变体是否是包括神经纤维缠结在内的潜在疾病病理学的危险因素。
研究全基因组关联研究中的 AD 易感性基因座是否会影响神经纤维缠结病理，并进一步确定该特征的新风险基因座。
设计、环境和参与者：对包括来自宗教秩序研究和拉什记忆与衰老项目的 725 名已故受试者的联合临床病理队列进行候选单核苷酸多态性分析和全基因组关联研究（2 项前瞻性、基于社区的研究），随后在独立的神经影像学队列中进行靶向验证，该队列包括来自多个临床和研究中心的 114 名受试者。
基于对来自多个大脑区域的经银染组织进行评估得出的神经纤维缠结病理负担的定量测量。验证基于免疫细胞化学的β-淀粉样蛋白负荷，并用 Pittsburgh 化合物 B 或 florbetapir 进行纤维状β-淀粉样蛋白正电子发射断层扫描成像复制。
除了先前报道的 APOE 和 CR1 基因座外，我们还发现 ABCA7（rs3764650；P = .02）和 CD2AP（rs9349407；P = .03）AD 易感性基因座与神经纤维缠结负担相关。此外，在我们全基因组关联研究的最高结果中，我们在淀粉样前体蛋白基因（APP，rs2829887）附近发现了一个与神经纤维缠结相关的新变体（P = 3.3×10-6）。该多态性与 2 个具有正常认知能力的成年人的独立队列中的死后β-淀粉样蛋白负荷以及纤维状β-淀粉样蛋白相关。
这些发现通过将经过验证的易感性等位基因与增加的神经纤维缠结病理相关联，增强了对 AD 危险因素的理解，并暗示 APP 基因座的常见遗传变异与 AD 的最早、无症状前阶段有关。
