GENETICS OF ALZHEIMER'S DISEASE IN ISRAELI ARABS

以色列阿拉伯人阿尔茨海默病的遗传学

• 批准号: 6533832
• 负责人: ROBERT PAUL FRIEDLAND
• 金额: $ 51.94万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533832
• 关键词: Alzheimer's disease; Israel; clinical research; cooperative study; disease /disorder proneness /risk; family genetics; gene environment interaction; genetic mapping; genetic polymorphism; genetic susceptibility; human subject; nervous system disorder epidemiology; neurogenetics

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.

描述（改编自申请人的摘要）：在基于 在研究AD的过程中，我们筛选了Wadi Ara的所有老年居民， 以色列北方特拉维夫附近的一个社区， 患病率（20.5%>60岁，60.5%>85岁）。这 患病率高于世界其他任何地方，即使在 年龄、教育和性别的调整，显然不是由于 APOE β-4等位基因频率增加。我们假设 这种遗传分离株中AD患病率的增加是由以下因素引起的： AD易感性等位基因，由于交配模式而过度表达 在这个只有少数创始人的封闭群体中。在本申请中，我们 建议广泛研究居住在这个社区的所有60岁以上的人， 年龄较大的人士（上次统计调查时人数为855人，包括168人 符合AD的NINDS/ADRDA标准）。我们将从每个实验对象身上 风险/保护因素数据（包括吸烟，血压，头部创伤， 教育、饮食、身心活动水平、职业和药物治疗 病史）和血液样本进行生化和DNA研究。家属举报 将用于构建详细的谱系。我们的科学目标是：（1） 估计流行病例的一级亲属中AD的终生风险 使用生存技术，并将这些估计与 认知正常受试者的亲属和其他AD患者的亲属 （2）使用一个或多个基因定位在该群体中引起AD的基因。 纯合性作图方法。为了快速筛选与 该疾病，一个AD影响和一个老年人非痴呆症，从每个几个 来自同一部落群体（hamula）的家庭将被基因分型为400 多态性微卫星标记间隔小于10 cM。嫌疑人 将通过对所有受试者单独进行基因分型来追踪染色体区域 标记间隔为2厘米。各种分析技术 包括参数（LOD得分）和非参数（受影响的相对， 同胞传递不平衡和等位基因频率依赖纯合性 作图）方法将被用来评估标记数据， （3）用SSCP/CSGE方法检测目标2中确定的候选区域的基因; 以及直接测序可能直接影响AD的多态性 （4）分析非遗传因素（单因素和多因素）对易感性的影响。 彼此组合以及与连锁的遗传标记或候选基因组合 多态性）对AD的风险。 识别特定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。结果从这个 研究可能对新治疗的开发产生直接影响，或 预防战略。

项目成果

Estimating the risk for conversion from mild cognitive impairment to Alzheimer's disease in an elderly Arab community.

• DOI: 10.3233/jad-142871
• 发表时间: 2015
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Inzelberg R;Massarwa M;Schechtman E;Strugatsky R;Farrer LA;Friedland RP
• 通讯作者: Friedland RP

What does the pediatrician need to know about Alzheimer disease?

关于阿尔茨海默病，儿科医生需要了解什么？

• DOI: 10.1097/dbp.0b013e3181a7ee83
• 发表时间: 2009
• 期刊: Journal of developmental and behavioral pediatrics : JDBP
• 作者: Friedland,RobertP;Brayne,Carol
• 通讯作者: Brayne,Carol

Aquaporin 4 molecular mimicry and implications for neuromyelitis optica.

• DOI: 10.1016/j.jneuroim.2013.04.015
• 发表时间: 2013-07-15
• 期刊: JOURNAL OF NEUROIMMUNOLOGY
• 影响因子: 3.3
• 作者: Vaishnav, Radhika A.;Liu, Ruolan;Chapman, Joab;Roberts, Andrew M.;Ye, Hong;Rebolledo-Mendez, Jovan D.;Tabira, Takeshi;Fitzpatrick, Alicia H.;Achiron, Anat;Running, Mark P.;Friedland, Robert P.
• 通讯作者: Friedland, Robert P.

Serum albumin concentration and cognitive impairment.

• DOI: 10.2174/156720510790274392
• 发表时间: 2010-02
• 期刊: Current Alzheimer research
• 影响因子: 2.1
• 作者: Llewellyn DJ;Langa KM;Friedland RP;Lang IA
• 通讯作者: Lang IA

Bovine spongiform encephalopathy and aquaculture.

牛海绵状脑病和水产养殖。

• DOI: 10.3233/jad-2009-1060
• 发表时间: 2009
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Friedland,RobertP;Petersen,RobertB;Rubenstein,Richard
• 通讯作者: Rubenstein,Richard