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.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种常见的，道具和最终的致命脑疾病 治疗只能提供最小的症状益处，不要阻止疾病的发展。 迫切需要新的药物靶标，这些靶标可以改善疗法 AD的遗传因子是载脂蛋白E基因的ε4变体（APOE4）。 APOE4强烈影响的优势发现新的遗传变异型会增加AD的风险或 降低广告的风险。 研究中心 - 将属于两个罕见类别的招募和研究参与者：认知正常 携带一两个副本的高风险APOE4（受保护的APOE4载体）和年轻患者的人 尽管没有携带APOE4基因，但在65岁之前的早期发作广告（EOAD）。 AD（步骤AD）队列中的极端表型将进行全外观测序及其外观将是 结合约4500个健康的旧对照和5000名AD患者的大型公开外来 AIM 1研究小组将寻找在受保护的APOE4载体中比在 AIM 2中的AD患者将寻找APOE4阴性EOAD患者的稀有遗传变异 在健康的较旧对照中，大多数步骤AD队列都会进行“深层表型” 和分子脑成像，脊髓液分析，免疫表型和参与者特异性的培养 神经元在AIM 3中，深度表型数据将开始了解 目标1和2中鉴定出的罕见保护性或因果变异。 在这项研究中确定和表征的将为设计潜在疾病设计的新型药物靶标提供新颖的药物 - 修改治疗。

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