Genetic Factors that Impact the Risk of Alzheimer's Disease

描述（由申请人提供）： 该应用程序解决了广泛的挑战领域（08）基因组学和特定的挑战主题，08- AG-101：遗传因素影响疾病风险因素随年龄的变化率。阿尔茨海默病（AD）是神经医学中最关键的未满足的需求，因为没有改善与之相关的痴呆或认知下降的疾病修饰疗法。超过500万美国人患有AD，并且除非开发出预防或延迟其发作的有效疗法，否则估计到2050年将有超过1600万美国人患有AD。本资助申请中描述的科学具有真实的变革潜力，可以清楚地识别影响AD发展速度的特定遗传因素，并确定预防性治疗方法和健康老龄化的方法。自1993年以来，APOE基因型与AD发病年龄之间的一般关系得到了充分的证明。最近的初步研究结果表明，AD的发病年龄是至少两个发病机制特异性基因APOE和TOMM 40的功能，每个基因具有多个决定因素，影响其蛋白质-蛋白质相互作用，位于相同的连锁不平衡（LD）区域。该提案开发并测试了特定变体与APOE 3顺式连接并与阿尔茨海默病（AD）发病年龄分布变化相关的范例。TOMM 40的最重要变体在骨架上或顺式至APOE <$3 LD区域进化，而不是顺式至APOE <$4 LD区域。编码线粒体外膜转位酶的TOMM 40基因与APOE蛋白相互作用，通过TOMM 40的构型和特定的APOE同种型进行修饰。由于这些发现，计划进行AD预防试验，以验证基于遗传的诊断的预测准确性，并测试特定的预防药物。随着年龄的增长，疾病风险的发展可能是许多小的遗传和环境因素的作用。所提出的方法为复杂疾病的遗传分析提供了一个新的框架，这些复杂疾病涉及来自几个相互作用基因的多个小信号，并且与深度测序数据的可用性以及公共领域长期纵向研究中可用的表型数据保持一致。线粒体功能的变化与许多衰老疾病相关：通过明确阐明与年龄相关疾病风险相关的TOMM 40遗传变异，将确定干预措施以延迟AD的发作。该计划的完成将大大增加遗传因素的证据基础，这些遗传因素会随着年龄的增长而影响AD的发展，测试AD预防方法，并提供强大的生物信息学工具来研究年龄相关风险背景下的其他临床相关疾病。阿尔茨海默病是一种严重的未满足的医疗需求，因为没有疾病修饰疗法可以改善与之相关的痴呆或认知能力下降。超过500万美国人患有AD，每年仅医疗保险就花费910亿美元。我们的研究建立在一个新的遗传学发现的基础上，以了解影响AD疾病风险随年龄变化率的遗传因素，这将导致发现阿尔茨海默病的预防性疗法。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08- AG-101: Genetic factors affecting rates of change in disease risk factors with age. Alzheimer's disease (AD) is the most critical unmet need in neurological medicine because there are no disease- modifying therapies that improve the dementia or cognitive decline associated with it. Over 5 million Americans suffer from AD and unless effective therapies for preventing or delaying its onset are developed, it is estimated that more than 16 million Americans will suffer from AD by 2050. The science described in this grant application has the real potential of being transformational to clearly identify specific genetic factors that affect the rate of development of AD and to identify preventive therapies and approaches for healthier aging. The general relationship between APOE genotype and the age of onset for AD is well-documented since 1993. Recent preliminary results show that age of onset of AD is a function of at least two pathogenesis specific genes APOE and TOMM40, each with multiple determinants that affect their protein-protein interactions, residing on the same linkage disequilibrium (LD) region. This proposal develops and tests the paradigm that specific variants are cis- linked to APOE ¿3 and are associated with changes in the age of onset distribution for Alzheimer's disease (AD). The most significant variants of TOMM40 have evolved on the backbone or cis to APOE ¿3 LD region, and not cis to the APOE ¿4 LD region. The TOMM40 gene, which codes for the translocase of the outer mitochondrial membrane, interacts with APOE proteins, modified by the configuration of TOMM40 and the specific APOE isoform. As a consequence of these findings, an AD prevention trial is planned to validate the predictive accuracy of the genetically-based diagnostic and to test a specific preventive drug. Development of disease risk with age may be a function of many small genetic and environmental factors. The proposed approach provides a novel framework for genetic analysis of complex diseases that involve multiple small signals from several interacting genes and is well-aligned with the availability of deep-sequencing data and with phenotypic data available from long-term longitudinal studies available in the public domain. Changes in mitochondrial function are associated with many diseases of aging: by clearly elucidating genetic variants in TOMM40 associated with age-related disease risk, interventions will be identified to delay the onset of AD. Completion of the program will greatly augment the evidence base for the genetic factors that influence the development of AD with age, test approaches for AD prevention and provide powerful bioinformatic tools to study other clinically-relevant diseases in the context of age-related risk. Alzheimer's disease is a critical unmet medical need because there are no disease-modifying therapies that improve the dementia or cognitive decline associated with it. Over 5 million Americans suffer from AD at a cost of $91 billion annually to Medicare alone. Our studies build on a new genetics discovery to understand genetic factors affecting the rate of change in disease risk for AD with age that will lead to the discovery of preventive therapies for Alzheimer's disease.