Genetic Factors that Impact the Risk of Alzheimer's Disease

描述(由申请人提供)： 本申请涉及广泛的挑战领域(08)基因组学和特定挑战主题08-AG-101：影响疾病风险因素随年龄变化的速率的遗传因素。阿尔茨海默病(AD)是神经医学中最关键的未得到满足的需求，因为没有任何疾病修改疗法可以改善与之相关的痴呆症或认知能力下降。超过500万美国人患有阿尔茨海默病，除非开发出预防或延缓其发病的有效疗法，否则到2050年，估计将有超过1600万美国人患有阿尔茨海默病。这项赠款申请中描述的科学具有真正的变革性潜力，可以清楚地确定影响阿尔茨海默病发展速度的特定遗传因素，并确定更健康老龄化的预防性治疗和方法。自1993年以来，载脂蛋白E基因与阿尔茨海默病发病年龄之间的一般关系已经得到了很好的证明。最近的初步结果表明，AD的发病年龄是至少两个致病特异性基因APOE和TOMM40的函数，每个基因都有影响其蛋白质-蛋白质相互作用的多个决定因素，位于相同的连锁不平衡(LD)区域。这一建议开发并测试了这样的范式，即特定的变异与APOE？3顺式关联，并与阿尔茨海默病(AD)发病年龄分布的变化有关。TOMM40最显著的变异是在主干或顺式到APOE？3LD区进化，而不是顺式到APOE？4LD区。TOMM40基因编码线粒体外膜转位酶，与APOE蛋白相互作用，受TOMM40构型和APOE亚型的修饰。作为这些发现的结果，计划进行一项AD预防试验，以验证基于基因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。提出的方法为复杂疾病的遗传分析提供了一个新的框架，这些疾病涉及来自几个相互作用的基因的多个小信号，并与深度测序数据的可用性以及公共领域可获得的长期纵向研究的表型数据很好地结合在一起。线粒体功能的改变与许多老年性疾病有关：通过明确阐明TOMM40与年龄相关疾病风险相关的遗传变异，将确定延缓AD发病的干预措施。该项目的完成将极大地增强影响AD随年龄发展的遗传因素的证据基础，测试AD预防的方法，并提供强大的生物信息学工具，在与年龄相关的风险背景下研究其他临床相关疾病。阿尔茨海默病是一种严重的未得到满足的医疗需求，因为目前还没有改善痴呆症或与之相关的认知能力下降的疾病修改疗法。超过500万美国人患有阿尔茨海默病，仅医疗保险一项每年就花费910亿美元。我们的研究建立在一项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的遗传因素，这将导致发现阿尔茨海默病的预防疗法。

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.