Phenotype and Genotype of Autosomal Dominant Alzheimer's Disease in Jalisco, Mexico

常染色体显性遗传性阿尔茨海默病患者或高危人群的研究 由于PSEN和APP基因突变导致的疾病(ADAD)对 我们对AD的总体理解。作为AD未来发展方向的ADAD传承人 突变可以可靠地预测，可以定义疾病的表型和发生的变化 在疾病的症状前阶段非常敏感，能够评估其他 影响病程的因素(例如，修改基因、假定的疾病修改效果 干预)。这样的研究是通过识别共享同一个家庭的大家庭来促进的 遗传易感性，这种方法在哥伦比亚的一个大家庭中得到了最好的实施 PSEN1(E280A)有一个常见的突变。PSEN1中一个独特突变的类似创始人效应 (A431E)和另一个在APP(V717I)上具有不同的ADAD导致突变的大家庭已经被 在墨西哥的哈利斯科州被发现，但到目前为止，对这些家庭的研究还不够深入。目标是 当前应用的目的是通过以下方式促进对这一人群的临床研究 哈利斯科的调查人员。这将通过以下具体目标来实现： 具体目标#1)通过以下方式确定和跟踪哈利斯科ADAD患者和高危人群的特征 年西方生物研究中心遗传学诊所之间的协调措施 瓜达拉哈拉、特帕蒂特兰瓜达拉哈拉大学综合诊所和南加州大学阿尔茨海默病 研究中心。通过提供基因测序技术和培训，我们还将使 这一群体的基因特征。 具体目标2)进行研究，以确定影响疾病开始年龄和 ADAD患者存在腿部僵硬。 具体目标#3)提高哈利斯科临床医生和研究人员的能力 为ADAD高危人群提供症状前遗传咨询，从而优化自主性 关于研究参与。 该项目将提高我们对ADAD的病理生理学的理解，并为 为未来对墨西哥这一信息丰富的人群的研究奠定基础。

The study of persons with or at-risk for genetically-determined autosomal dominant Alzheimer’s disease (ADAD) due to mutations in the PSEN and APP genes has made tremendous contributions to our understanding of AD in general. As the future development of AD in persons inheriting ADAD mutations can be reliably predicted, one can define the disease phenotype and changes occurring during the presymptomatic phase of the disease with great sensitivity, enabling the evaluation of other factors influencing disease course (e.g. modifying genes, effects of putative disease-modifying interventions). Such research is facilitated by the identification of large families sharing the same genetic predisposition, an approach that has been best implemented in an extended family in Colombia with a common mutation in PSEN1 (E280A). A similar founder effect for a distinct mutation in PSEN1 (A431E) and another large family with a different ADAD-causing mutation in APP (V717I) has been identified in the State of Jalisco in Mexico but to date these families have been understudied. The goal of the current application is to facilitate the performance of clinical studies of this population by investigators in Jalisco. This will be achieved through the following specific aims: Specific Aim #1) To characterize and follow persons with and at-risk for ADAD in Jalisco by harmonizing measures between the Centro de Investigación Biomédica de Occidente Genetics clinic in Guadalajara, the University of Guadalajara Polyclinic in Tepatitlan, and the USC Alzheimer’s Disease Research Center. By providing gene-sequencing technology and training, we will also enable the genetic characterization of this population. Specific Aim #2) To perform studies to identify genes that affect the age of disease onset and the presence of leg stiffness in ADAD. Specific Aim #3) To improve the ability of clinicians and researchers in Jalisco to deliver presymptomatic genetic counseling for persons at-risk for ADAD, thus optimizing autonomy with regards to research participation. This project will improve our understanding of the pathophysiology of ADAD and lay the groundwork for future studies of this informative population in Mexico.