GENETICS OF ALZHEIMER'S DISEASE IN ISRAELI ARABS

描述(改编自申请人的摘要)：以人口为基础 对AD的研究，我们已经对阿拉伯人Wadi Ara的所有老年居民进行了筛查 以色列北部特拉维夫附近的社区，观测到了异常高的 患病率(60岁组的20.5%，85岁组的60.5%)。这 流行率比世界其他任何地方都要高，即使在 根据年龄、教育程度和性别进行调整，显然不是因为 APOE epsilon-4等位基因频率增加。我们假设 这种遗传分离株中AD患病率的增加是由于存在 由于交配模式而过度表达的AD易感等位基因 在这个封闭的人群中，创始人寥寥无几。在此应用程序中，我们 建议广泛研究居住在这个社区的所有60岁和 老年人(上次调查时为855人，包括168人 符合AD的NINDS/ADRDA标准)。我们将从每个受试者那里获得 风险/保护因素数据(包括吸烟、血压、头部创伤、 教育、饮食、体力和精神活动水平、职业和药物 病史)和用于生化和DNA研究的血液样本。家庭告密者 将被用来构建详细的家谱。我们的科学目标是：(1) 估计阿尔茨海默病流行病例一级亲属的生活风险 使用生存技术，并将这些估计值与 认知正常受试者亲属及其他地区AD患者亲属 (2)在该种群中定位导致AD的基因(S) 纯合子作图方法。为了快速筛选与 这种疾病，一名AD患者和一名老年非痴呆患者分别来自几个 来自同一部落群体(哈姆拉)的家庭将进行400人的基因分型 多态微卫星标记间距小于10 cM。疑犯 将通过对所有受试者单独进行基因分型来寻找染色体区域。 每隔2厘米间隔设置标记。各种分析技术 包括参数(LOD评分)和非参数(受影响的亲属、 SIB传递不平衡与等位基因频率相关的纯合性 测绘)方法将用来评估标记数据，以便与 (3)用SSCP/CSGE检测AIM 2中确定的候选区域的基因； 对可能直接影响AD的多态进行直接测序 易感性；(4)分析非遗传因素(单独和间接)的影响 相互结合以及与连锁遗传标记或候选基因的结合 多态)对AD风险的影响。 确定特定的基因并阐明其机制和性质 基因与环境的相互作用将是一项重大成就。由此产生的结果 研究可能会对新疗法的开发产生直接影响 预防策略。

DESCRIPTION (Adapted from the Applicant's Abstract): In a population based study of AD, we have screened all elderly residents of Wadi Ara, an Arab community near Tel Aviv in northern Israel, and observed an unusually high prevalence (20.5% of those >60 years, 60.5% of those >85 years). This prevalence is higher than that found anywhere else in the world, even after adjustment for age, education and gender, and apparently is not due to increased frequency of the APOE epsilon-4 allele. We hypothesize that the increased prevalence of AD in this genetic isolate is caused by the presence of AD susceptibility alleles which are over-represented because of mating patterns in this closed population which has few founders. In this application we propose to study extensively all persons residing in this community ages 60 and older (numbering 855 at the time of the last survey including 168 persons meeting NINDS/ADRDA criteria for AD). We will obtain from each subject risk/protective factor data (including smoking, blood pressure, head trauma, education, diet, physical and mental activity levels, occupation and medication history) and blood samples for biochemical and DNA studies. Family informants will be used to construct detailed pedigrees. Our scientific aims are: (1) Estimate the life-time risk of AD in first-degree relatives of prevalent cases using survival techniques and compare these estimates to those obtained for relatives of cognitively normal subjects and for relatives of AD cases in other populations; (2) Localize the gene(s) causing AD in this population using a homozygosity mapping approach. In order to rapidly screen for markers linked to the disease, one AD affected and one elderly nondemented from each of several families from the same tribal group (hamula) will be genotyped with 400 polymorphic microsatellite markers spaced less than 10 cM apart. Suspect chromosomal regions will be pursued by genotyping all subjects individually with markers spaced at 2 cM intervals. A variety of analytical techniques including both parametric (lod score) and non-parametric (affected relative, sib-transmission-disequilibrium and allele-frequency-dependent homozygosity mapping) approaches will be employed to assess the marker data for linkage to AD; (3) Examine genes from candidate regions identified in aim 2 by SSCP/CSGE; and direct sequencing for polymorphisms which may directly influence AD susceptibility; (4) Analyze the effects of non-genetic factors (singly and in combination with each other and with linked genetic markers or candidate gene polymorphisms) on risk of AD. Identifying specific genes and elucidating their mechanisms and the nature of gene/environment interactions will be a major achievement. Results from this study may have immediate impact on the development of new treatment or prevention strategies.