The Stanford Extreme Phenotypes in Alzheimer's Disease (StEP AD) Cohort

斯坦福阿尔茨海默病极端表型 (StEP AD) 队列

• 批准号: 10431761
• 负责人: Michael D Greicius
• 金额: $ 24.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431761
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein Precursor; Apolipoprotein E; Autopsy; Biological; Biological Assay; Brain Diseases; Brain imaging; Categories; Cerebrospinal Fluid; Cognitive; Databases; Disease; Early Onset Alzheimer Disease; Genes; Genetic; Genetic Diseases; Genetic Risk; Goals; Heritability; Immunophenotyping; Induced pluripotent stem cell derived neurons; Lead; Molecular; Neurodegenerative Disorders; Neurons; Participant; Pathogenesis; Pathway interactions; Patients; Persons; Phenotype; Positron-Emission Tomography; Proteomics; Research; Research Personnel; Resources; Sampling; Single Nucleotide Polymorphism; Source; Twin Studies; Universities; Variant; autosomal dominant mutation; base; brain tissue; causal variant; cohort; design; disorder risk; drug development; early onset; exome; exome sequencing; expectation; falls; gene discovery; genetic risk factor; genetic variant; genome wide association study; high risk; innovation; insight; new therapeutic target; novel; phenotypic data; presenilin-1; presenilin-2; rare variant; recruit; resilience; targeted sequencing

Project Summary/Abstract Alzheimer's disease (AD) is a common, progressive, and ultimately fatal brain disease. Currently approved treatments provide only minimal symptomatic benefits and do not stop the disease from progressing. The field is in dire need of novel drug targets which could lead to disease-modifying therapies. The most common genetic risk factor for AD is the ε4 variant of the apolipoprotein E gene (APOE4). The current study will take advantage of the strong effect of APOE4 to discover new genetic variants that either increase risk for AD or reduce risk for AD. The research team—based at Stanford University but including collaborators at 13 other research centers—will recruit and study participants that fall into one two rare categories: cognitively normal people carrying one or two copies of the high risk APOE4 gene (protected APOE4 carriers) and young patients who early-onset AD (EOAD) before age 65 despite not carrying APOE4 gene. These subjects, the Stanford Extreme Phenotypes in AD (StEP AD) cohort, will undergo whole-exome sequencing and their exomes will be combined with large, publicly available exomes from ~4500 healthy older controls and ~5000 AD patients. In Aim 1 the research team will look for rare genetic variants seen more often in protected APOE4 carriers than in AD patients. In Aim 2 the team will look for rare genetic variants seen in APOE4-negative EOAD patients but not in healthy older controls. Most of the StEP AD cohort will undergo “deep phenotyping” to include structural and molecular brain imaging, spinal fluid analysis, immunophenotyping, and culturing of participant-specific neurons. In Aim 3, the deep phenotyping data will be used to begin to understand the molecular effects of the rare protective or causal genetic variants identified in Aims 1 and 2. Rare but powerful genetic variants identified and characterized in this study will provide novel drug targets for the design of potentially disease- modifying treatments.

项目总结/摘要 阿尔茨海默病（AD）是一种常见的、进行性的、最终致命的脑部疾病。目前批准 治疗仅提供最小的症状益处，并且不能阻止疾病的进展。领域 迫切需要新的药物靶点，这可能导致疾病改善疗法。最常见的 AD的遗传风险因素是载脂蛋白E基因（APOE 4）的ε4变体。目前的研究将 APOE 4的强大作用的优势，发现新的遗传变异，要么增加AD的风险， 降低AD风险。该研究小组设在斯坦福大学，但包括其他13个合作者。 研究中心将招募和研究属于两种罕见类别的参与者：认知正常 携带一个或两个高风险APOE 4基因拷贝的人（受保护的APOE 4携带者）和年轻患者 未携带APOE 4基因的65岁以前早发性AD（EOAD）患者。这些科目，斯坦福大学 AD中的极端表型（StEP AD）队列将经历全外显子组测序，并且其外显子组将被测序。 与来自~4500名健康老年对照和~5000名AD患者的大型公开可用外显子组组合。在 研究小组将寻找在受保护的APOE 4携带者中更常见的罕见遗传变异， AD患者。在目标2中，研究小组将寻找在APOE 4阴性EOAD患者中观察到的罕见遗传变异， 而不是健康的老年对照组。大多数StEP AD队列将进行“深度表型分析”，以包括结构 以及分子脑成像、脊髓液分析、免疫表型分析和培养参与者特异性 神经元在目标3中，深度表型数据将用于开始了解 在目标1和2中发现的罕见的保护性或致病性遗传变异。罕见但强大的遗传变异 在这项研究中鉴定和表征的药物将为设计潜在的疾病提供新的药物靶点， 修改治疗方法。

项目成果

Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease.

• DOI: 10.1212/nxg.0000000000000647
• 发表时间: 2022-03
• 期刊: Neurology. Genetics
• 作者: Eger SJ;Le Guen Y;Khan RR;Hall JN;Kennedy G;Zaharchuk G;Couthouis J;Brooks WS;Velakoulis D;Napolioni V;Belloy ME;Dalgard CL;Mormino EC;Gitler AD;Greicius MD
• 通讯作者: Greicius MD