PLASMA A BETA AS A SURROGATE GENETIC MARKER FOR LOAD

描述：APP、PS1和PS2基因突变的鉴定 导致早发性家族性阿尔茨海默病(AD)的证据 这些突变都增加了Abeta42，并发现了一种关联 载脂蛋白E4与晚发性阿尔茨海默病之间的关系 提高了我们对阿尔茨海默氏症的理解。然而，很明显， 迟发性阿尔茨海默病的大部分遗传风险仍未得到解释。 识别影响迟发性阿尔茨海默病的其他基因的当前策略 疾病往往因为困难而取得有限的成功 与获得晚发家庭有足够的能力 可靠的连锁分析。遗传学研究使用了大量的小分子 为了增加分析的能力，家庭或兄弟姐妹对也是 然而，目前正在由几个小组执行， 不同的研究发现，阳性基因座的非复制具有 继续。也很难识别与生物相关的 利用这种类型的小家庭/同胞对识别的基因座的遗传变异性 分析，因为候选区域往往很大，而且定义不清。 在这项建议中，我们描述了高水平的血浆ABETA水平可以用作 代孕表型增加晚发性AD家庭的能力 不仅特定的染色体区域与疾病有可靠的联系，而且 也有助于识别遗传变异性，即 对血浆Abeta42升高和糖尿病风险增加负责 患上阿尔茨海默氏症。

DESCRIPTION: The identification of mutations in the APP, PS1, and PS2 genes that cause early-onset familial Alzheimer's disease (AD), the demonstration that these mutations all increase Abeta42, and the discovery of an association between Apolipoprotein E4 and late-onset Alzheimer's disease have dramatically improved our understanding of Alzheimer's disease. It is clear, however, that much of the genetic risk in late onset Alzheimer's disease remains unexplained. Current strategies to identify other genes that affect late-onset Alzheimer's disease have met with limited success often because of the difficulty associated with obtaining late-onset families with sufficient power for reliable linkage analysis. Genetic studies using large numbers of small families or sib-pairs, to increase the power of the analysis, are also currently being performed by several groups however difficulties with the non-replication of positive loci, identified by different studies, has continued. It will also be difficult to identify the biologically relevant genetic variability using loci identified by this type of small family/sib pair analysis, as candidate regions tend to be large and poorly defined. In this proposal we describe how high plasma ABeta levels can be used as a surrogate phenotype to increase the power of late-onset AD families allowing not only the reliable linkage of a specific chromosomal region with disease but also facilitating the identification of the genetic variability that is responsible for the increased plasma Abeta42 and for the increased risk of developing Alzheimer's disease.