DOWN SYNDROME & ALZHEIMER DISEASE--FAMILIAL AGGREGATION

阿尔茨海默病是老年相关性痴呆最常见的原因。 痴呆症，影响多达200万人。本研究将 调查假设，有共同的遗传影响， 唐氏综合征（DS）和阿尔茨海默病（AD）的易感性， 检查AD患者亲属中AD风险的异质性， DS.超过90%的唐氏综合征三体与非- 母配子分离事件。如果有共享 AD和DS的易感因素，AD频率增加 对于母源性DS病例， 与他们的父系亲属相比。此外，A的发生 唐氏综合征出生于年轻母亲可能表明对 加速衰老，不仅表现在DS患儿的出生 而且在她的家庭中也有更高的患AD的风险。我们假设 DS先证者的母系亲属由年轻母亲（小于35岁）所生 与35岁以上）将处于AD的较高风险中，并且他们的AD可能 在发病年龄较早时就表现出来。 我们将确定DS核型（三体，易位，嵌合）， 确定非- 在DS病例中，使用 结合细胞遗传学和分子多态性研究。我们将 确定AD的频率是否在第一和第二阶段增加， 与DS患者的亲属相比， 对照组为无DS的发育性残疾人。 亲属中痴呆症的确定将在两个 阶段可能的AD病例将通过半结构化的 与先证者3名亲属面谈。然后我们将评估 疑似AD病例和所有亲属的随机样本， 神经学和神经心理学检查以获得鉴别诊断 痴呆症的诊断和病历审查或死亡证明 审查.我们将使用寿命表分析和逻辑回归， 比较AD的风险：1）DS病例的亲属和 对照组; 2）母系来源的21三体DS的母系亲属 病例及其父系亲属，以及相应的母系亲属， 对照组和对照组的父系亲属; 3）年轻和年长的亲属 出生时母亲患有DS。如果家族聚集 建立，通过与AD的联系识别诱发因素 这些家族中的多态性DNA标记将是下一个重要的 步

Alzheimer disease is the most common cause of old-age-associated dementia, affecting as many as 2 million people. This study will investigate the hypothesis that there are shared genetic influences on susceptibility to Down syndrome (DS) and Alzheimer disease (AD) and will examine heterogeneity of risk for AD among relatives of individuals with DS. More than 90% of Down syndrome trisomies are associated with a non- disjunction event in maternal gametes. Therefore, if there are shared susceptibility factor(s) for AD and DS, an increased frequency of AD would be expected in maternal relatives for maternally derived DS cases, compared with their paternal relatives. In addition, the occurrence of a Down syndrome birth to a younger mother may indicate a susceptibility to accelerated aging, expressed not only in the birth of a child with DS but also in a higher risk for AD in her family. We hypothesize that maternal relatives of DS probands born to younger mothers (less than 35 vs 35+ years) will be at higher risk for AD, and that their AD may be expressed at earlier ages of onset. We will determine DS karyotype (trisomy, translocation, mosaicism) and identify parental origin (maternal versus paternal) of the non- disjunction event leading to trisomy in the DS cases, using a combination of cytogenetic and molecular polymorphism studies. We will determine whether the frequency of AD is increased in first- and second- degree relatives of individuals with DS compared with relatives of a matched control group of developmentally disabled people without DS. Ascertainment of dementia among relatives will be accomplished in two stages. Possible cases of AD will be identified by a semi-structured interviewed with 3 relatives of the proband. We will then evaluate the suspected cases of AD and a random sample of all relatives by neurological and neuropsychological examination to obtain a differential diagnosis of dementia and by medical record review or death certificate review. We will use lifetable analysis and logistic regression to compare risk for AD in: 1) relatives of DS cases and relatives of controls; 2) maternal relatives of maternally derived trisomy 21 DS cases and their paternal relatives, and in the corresponding maternal and paternal relatives of controls; 3) relatives of younger and older mothers at birth of individuals with DS. If familial aggregation is established, identification of a predisposing factor by linkage of AD and polymorphic DNA markers in these families would be an important next step.