DOWN SYNDROME & ALZHEIMER DISEASE--FAMILIAL AGGREGATION

阿尔茨海默病是与老年相关的最常见的原因 痴呆症，影响多达200万人。这项研究将 调查有共同遗传影响的假说 对唐氏综合征(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 母体配子中的分离事件。因此，如果有共享的 AD的易感因素(S)和DS，AD的频率增加 可能会出现在母亲衍生的DS病例的母亲亲属中， 与它们的父系亲属相比。此外，还会发生 较年轻的母亲生下唐氏综合症可能意味着易患上 加速衰老，不仅表现在患有DS的孩子的出生 而且在她的家庭中患AD的风险也更高。我们假设 较年轻母亲(不到35岁)所生DS先证者的母亲亲属 VS 35岁以上)将面临更高的AD风险，并且他们的AD可能 在发病年龄较早时表现出来。 我们将确定DS核型(三体、易位、嵌合体)和 确定非父母来源(母系与父系) 在DS病例中导致三体的分离事件，使用 细胞遗传学和分子多态研究相结合。我们会 确定AD的频率是否在第一-和第二- DS患者的学位亲属与 对照组为无发育障碍的发育障碍者。 确定亲属中的痴呆症将在两个月内完成 各阶段。AD的可能病例将通过半结构化的 与先证者的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抽样 神经学和神经心理学检查以获得区别 痴呆症的诊断和通过病历审查或死亡证明 复习一下。我们将使用寿命分析和Logistic回归分析来 比较以下方面的AD风险：1)DS患者的亲属和 对照；2)母系衍生21-DS三体的母系亲属 病例及其父系亲属，以及在相应的母亲 和对照的父系亲属；3)年轻和年长的亲属 DS患者出生时的母亲。如果家族聚集性是 阿尔茨海默病易感因素的建立和鉴定 这些家族中的多态DNA标记将是下一个重要的 一步。

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.