Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp)

描述（由申请人提供）：最近对阿尔茨海默病的观察表明，影响大脑病理特征与临床症状之间关系的因素在疾病过程中起着重要作用。首先，超过25%的非痴呆老年人的脑部病理与已知的阿尔茨海默病患者难以区分。其次，在临床诊断为疾病的患者中，明显存在“快速进展者”和“缓慢进展者”。我们将对关系位点（rQTL）进行全基因组筛选，这些关系位点（rQTL）修改脑脊液α 42水平与病例/对照状态之间的已知关系（相关性），从而筛选解释观察到的非痴呆个体阿尔茨海默病病理的位点。通过对我们的模型进行轻微调整，我们还可以筛选基因座，这些基因座可以改变脑脊液α 42水平和tau水平之间的已知关系，并可能解释疾病进展速度的变化。为了进行这些分析，我们收集了2000多个具有脑脊液生物标志物测量、临床评估和全基因组标记数据的样本，用于发现和近1000个具有脑脊液生物标志物测量和临床评估的样本，用于复制（基因分型将作为本提案的一部分完成）。然后，我们将在大约20,000例病例和30,000例对照（其中超过1900例具有疾病进展的纵向测量）中测试复制变异与阿尔茨海默病的风险和进展率的关联。正如我们的初步分析所表明的那样，这种有希望的方法将利用同类中最大的样本，通过多效性和相互作用效应来识别与阿尔茨海默病和阿尔茨海默病生物标志物相关的遗传变异。这将提供洞察变异在重要的疾病相关的过程，如蛋白质聚集和炎症和免疫反应。这些发现可能对其他蛋白质聚集和/或蛋白质错误折叠疾病具有重要意义。

DESCRIPTION (provided by applicant): Recent observations in Alzheimer's disease suggest that factors, which influence the relationship between pathological features in the brain and clinical symptoms, play a significant role in the disease process. First, more than 25% of non-demented, elderly individuals have brain pathology that is indistinguishable from known Alzheimer's disease individuals. Second, among those with a clinical diagnosis of disease there are clearly "fast progressors" and "slow progressors". We will perform a genome-wide screen for relationship loci (rQTL) that modify the known relationship (correlation) between cerebrospinal fluid A�42 levels and case/control status, thus screening for loci that explain the observation of non-demented individuals with Alzheimer's disease pathology. With slight adjustments to our models we can also screen for loci, which modify the known relationship between cerebrospinal fluid A�42 levels and tau levels, and may explain the variation in the rate of progression of disease. For these analyses we have assembled over 2,000 samples with cerebrospinal fluid biomarker measurements, clinical evaluations, and whole-genome marker data for discovery and nearly 1000 samples with cerebrospinal fluid biomarker measurements and clinical evaluations for replication (genotyping to be completed as part of this proposal). We will then test the replicated variants for association with risk and rate of progression of Alzheimer's disease in approximately 20,000 cases and 30,000 controls (over 1900 of which have longitudinal measurements of disease progression). As demonstrated by our preliminary analyses, this promising approach will leverage the largest sample of its kind to identify genetic variation that is associated with Alzheimer's disease and Alzheimer's disease biomarkers via pleiotropic and interaction effects. This will provide insight into variation in important disease related processes such as protein aggregation and inflammatory and immune response. These findings are likely to be important for other protein aggregation and/or protein misfolding diseases.