Epidemiology of Familial Late-Onset Alzheimer's Disease

描述（由申请人提供）：当前研究复杂疾病如晚发性阿尔茨海默病（LOAD）的遗传影响的主题是“常见疾病，常见变异”假说。该理论认为，多种常见变异是导致LOAD的根本原因。该项目的目的是验证和量化这些新发现的遗传风险因素的临床影响，即PICALM， CLU, BIN1， MS4A基因簇，CD33, CD2AP， ABCA7和EPHA1的snp，使用通过国家衰老-晚发性阿尔茨海默病家族研究研究所（ia - load）招募的多重家族。这些家族中丰富的表型和分子遗传信息的可用性使我们处于一个独特的位置，以估计这些变异的基因型相对风险，以及最近GWA荟萃分析和目前正在进行的外显子组测序项目中发现的其他变异。提出的纵向随访，确定其他亲属的特征，确定先前的危险因素，以及招募尸体解剖也将极大地受益

DESCRIPTION (provided by applicant): A current theme underlying research for genetic influences in complex diseases such as late onset Alzheimer's disease (LOAD) is the "common disease, common variant" hypotheses. This theory posits that multiple common variants underlie the cause of LOAD. The goals of this project is to validate and quantify the clinical impact of these newly identified genetic risk factors, namely SNPs in PICALM, CLU, BIN1, MS4A gene clusters, CD33, CD2AP, ABCA7 and EPHA1 using the multiplex families recruited through the National Institute on Aging-Late Onset Alzheimer's Disease Family Study (NIA-LOAD). The availability of rich phenotypic and molecular genetic information in these families places us in a unique position to estimate the genotype relative risks for these variants and others identified in the recent GWA meta-analyses and the exome sequencing projects currently underway. The proposed longitudinal follow-up, the characterization of additional relatives with ascertainment of antecedent risk factors, and recruitment for autopsy will also greatly benefit the field by expanding the scientific value of the NIA-LOAD Family Study. This resource of families provides distinct advantages for characterizing the impact of genetic variants on disease risk. First, multiplex families are likely to be enriched for genetic variants associated with increased risk, providing increased statistical power to estimate the effects. Second, analysis of these families provides insight into the remaining unknown genetic influences (i.e., the "residual heritability) as well as antecedent modifying factors that interact with identified genetic variant to influence disease risk. Third, family members at risk are followed at regular intervals, facilitating prospective investigation of the effects of the genetic variants on age-at-onset as wel as the modifying effects of antecedent risk and protective factors. Finally, family data can provide information regarding the influence of known variants on the rate of disease progression and the residual heritability of disease progression. We will address two overall hypotheses: 1) the risk of late onset Alzheimer's disease differs among families and is related to the inheritance of specific genetic variants. The impact of these variants on disease risk is greater in multiplex families than in sporadic cases. Phenocopies and incomplete penetrance in families are related to modifying risk factors. 2) The rate of disease progression is genetically influenced, and related to the same genetic variants that influence disease susceptibility.