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）， 这些突变都增加了Abeta 42，并且发现了一种关联 载脂蛋白E4和晚发性阿尔茨海默病之间的联系 提高了我们对阿尔茨海默病的认识。然而，很明显， 迟发性阿尔茨海默病的大部分遗传风险仍然无法解释。 目前的策略，以确定其他基因，影响晚发性阿尔茨海默氏症 疾病的成功有限，往往是因为 与获得具有足够能力的晚发型家族相关， 可靠的连锁分析。基因研究使用大量的小 家庭或同胞对，以增加分析的力量，也是 目前正在由几个团体执行，但困难与 不同的研究表明，阳性基因座的非复制性， 持续期间内的也很难确定生物学相关的 遗传变异性使用由这种类型的小家族/同胞对鉴定的基因座 分析，因为候选区域往往是大的和不明确的。 在这个建议中，我们描述了如何高的血浆ABeta水平可以被用作一个 替代表型，以增加迟发性AD家族的能力， 不仅是特定染色体区域与疾病的可靠联系， 也有助于识别遗传变异性， 导致血浆Abeta 42增加， 患上了老年痴呆症

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.