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

墨西哥哈利斯科州常染色体显性阿尔茨海默病的表型和基因型

• 批准号: 10475287
• 负责人: JOHN M RINGMAN
• 金额: $ 65.13万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475287
• 关键词: Adult; Advocacy; Affect; Age; Age of Onset; Alzheimer' s Disease; Amyloid Beta A4 Precursor Protein; C9ORF72; CSF1R gene; California; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Cognitive; Collaborations; Colombia; Data Set; Development; Disease; Elements; Ethics; Evaluation; Extended Family; Family; Founder Effect; Functional disorder; Funding; Future; Gender; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Screening; Genetic study; Genotype; Goals; Impaired cognition; Infrastructure; Inherited; International; Intervention; Leg; Measures; Medical Genetics; Mentorship; Mexican; Mexico; Mutation; Neurodegenerative Disorders; Neurologic; Neuropsychology; Onset of illness; Pathogenicity; Patient Care; Performance; Persons; Phase; Phenotype; Population; PrP gene; Prevention; Procedures; Protocols documentation; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Risk; Spastic Paraparesis; Standardization; System; Technology; Testing; Training; United States National Institutes of Health; Universities; Work; autosomal dominant Alzheimer' s disease; base; behavioral phenotyping; cognitive testing; cohort; disease phenotype; disease-causing mutation; evidence base; exome sequencing; familial Alzheimer disease; genetic testing; genetic variant; improved; mutation carrier; presenilin-1; presenilin-2; presymptomatic testing; prospective; research clinical testing; research study; standardize measure

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.

对遗传学确定的常染色体显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ADAD疾病（ADAD）对人类的健康做出了巨大贡献。 我们对AD的理解。作为未来发展的AD在人继承ADAD 突变可以可靠地预测，人们可以定义疾病表型和发生的变化， 在疾病的症状前阶段具有很高的敏感性，使其他评估 影响疾病进程的因素（例如修饰基因，假定的疾病修饰基因的作用） 干预）。这种研究是通过确定大家庭共享相同的便利。 遗传易感性，这种方法在哥伦比亚的大家庭中得到了最好的实施， PSEN1（E280A）突变。PSEN1中一个独特突变的类似奠基者效应 （A431E）和另一个在APP中具有不同ADAD引起突变（V717 I）的大家族， 在墨西哥的哈利斯科州发现了这些家庭，但迄今为止，这些家庭尚未得到充分研究。目标 本申请的目的是通过以下方式促进该人群的临床研究 调查人员在哈利斯科。这将通过以下具体目标实现： 具体目标#1）通过以下方式描述和跟踪哈利斯科的ADAD患者和有ADAD风险的患者： 协调西方遗传学生物医学研究中心与 瓜达拉哈拉，瓜达拉哈拉大学特帕提特兰综合医院，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 这个群体的遗传特征。 具体目标#2）进行研究以鉴定影响疾病发作年龄和疾病发生的基因。 ADAD中存在腿部僵硬。 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风险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，并奠定 为今后对墨西哥这一信息丰富的人口进行研究奠定了基础。