Beyond APOE: A Polygenic Approach to Risk for Alzheimer's Disease in Humans

超越 APOE：降低人类阿尔茨海默病风险的多基因方法

• 批准号: 9110798
• 负责人: Theresa M. Harrison
• 金额: $ 2.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110798
• 关键词: Accounting; Affect; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Assessment tool; Atrophic; Behavioral; Biological Neural Networks; Brain; Candidate Disease Gene; Caring; Characteristics; Clinical; Clinical Trials Design; Cognitive; Consensus; Controlled Clinical Trials; Data; Data Set; Dementia; Development; Diagnosis; Disease; Elderly; Elements; Enrollment; Episodic memory; Family history of; Family member; Future; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genomics; Genotype; Goals; Health; Heritability; Hippocampus (Brain); Human; Human Genome Project; Image; Impaired cognition; Individual; Intervention Trial; Laboratories; Laboratory Study; Learning; Left; Literature; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Memory; Methods; Modeling; Molecular; Molecular Biology; Onset of illness; Other Genetics; Pathogenesis; Patients; Performance; Phenotype; Prevention strategy; Procedures; Research; Research Design; Research Personnel; Resolution; Resources; Risk; Sample Size; Sampling; Single Nucleotide Polymorphism; Site; Specialized Center; Structure; Susceptibility Gene; Techniques; Testing; Therapeutic Intervention; Thick; Time; Twin Studies; Variant; Visual; Work; angular gyrus; apolipoprotein E-4; base; brain health; cerebral atrophy; clinically relevant; cognitive testing; cohort; data sharing; design; disorder prevention; effective intervention; genetic risk factor; genome wide association study; high risk; hippocampal atrophy; hippocampal subregions; human disease; imaging biomarker; indexing; interdisciplinary approach; neuroimaging; neuron loss; non-invasive imaging; prevent; relating to nervous system; research study; risk variant; tool

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia, accounting for 50-75% of all cases. Clinical AD affects episodic memory first, but eventually results in global dementia, leaving patients severely cognitively impaired and unable to care for themselves. Marked brain atrophy, especially in the hippocampus, and disruption of normal structural and functional neural networks are all associated with AD. It is likely that thes changes are extremely difficult to reverse. Therefore, AD prevention strategies are needed to preserve brain health and prevent the neuronal loss that leads to morphological changes in the brain and cognitive decline. A key component of any disease-specific prevention strategy is the reliable identification of individuals who are at risk for developing the disease so that they may be enrolled in controlled clinical trials. Twin studies reveal that the heritability of AD is 60-80, and APOE genotype accounts for about 50% of the variation in heritability. Thus, there is a significant portion of heritability that is explained by other genes. AD risk genes identified in genome wide association studies and through bench experiments are potential candidates and provide possible targets for studying the molecular basis of AD pathogenesis. In addition, these genes may have clinical relevance in helping to identify individuals who are likely to develop AD. This proposal suggests using non-invasive imaging and cognitive measures to assess this potential clinical use. The goal is to ascertain whether non-APOE AD risk genes have additional clinical prediction value by creating indices of polygenic risk based on APOE status, family history of AD and additional AD risk genes. The predictive power of these scores will be assessed against multiple metrics of decline in a cohort of cognitively healthy older adults. Decline over a two-year period will be estimated based on early AD-related changes in brain structure that are supported in the literature, including cortical thinning within the hippocampus and across AD-vulnerable regions of the cortical ribbon (e.g., the precuneus, angular gyrus and others). Cognitive decline will be measured by creating memory domain Z-scores (derived from multiple memory performance measures, including recall of word lists, stories and visual word pairs) for each time point. Polygenic risk score may be a more sensitive predictor of decline in these metrics than APOE status alone. In order to identify individuals at highest risk for AD, thi proposal suggests a multidisciplinary approach that integrates multiple genetic risk factors with imaging and behavioral data. Taken together, these studies will provide a better understanding of the neural substrates and cognitive (memory) consequences of genetic risk for AD.

描述（由申请人提供）：阿尔茨海默病 (AD) 是最常见的痴呆症，占所有病例的 50-75%。临床AD首先影响情景记忆，但最终导致全身性痴呆，使患者严重认知受损且无法照顾自己。明显的脑萎缩（尤其是海马体）以及正常结构和功能神经网络的破坏都与 AD 相关。这些变化很可能极难逆转。因此，需要采取 AD 预防策略来保护大脑健康并防止神经元丢失，从而导致大脑形态变化和认知能力下降。 任何特定疾病预防策略的一个关键组成部分是可靠地识别有患该疾病风险的个体，以便他们可以参加对照临床试验。双胞胎研究表明AD的遗传力为60-80，APOE基因型约占遗传力变异的50%。因此，遗传力的很大一部分是由其他基因解释的。在全基因组关联研究和实验室实验中鉴定出的 AD 风险基因是潜在的候选基因，并为研究 AD 发病机制的分子基础提供了可能的目标。此外，这些基因可能具有临床相关性，有助于识别可能患 AD 的个体。该提案建议使用非侵入性成像和认知措施来评估这种潜在的临床用途。 目标是通过根据 APOE 状态、AD 家族史和其他 AD 风险基因创建多基因风险指数，确定非 APOE AD 风险基因是否具有额外的临床预测价值。这些分数的预测能力将根据一组认知健康的老年人的下降的多个指标进行评估。两年期间的下降将根据文献支持的早期 AD 相关的大脑结构变化进行估计，包括海马内和 AD 易受影响的皮质带区域（例如，楔前叶、角状皮质）的皮质变薄。回等）。认知能力下降将通过为每个时间点创建记忆域 Z 分数（源自多种记忆性能测量，包括单词列表、故事和视觉单词对的回忆）来测量。与单独的 APOE 状态相比，多基因风险评分可能是这些指标下降的更敏感的预测因子。 为了识别 AD 风险最高的个体，该提案提出了一种多学科方法，将多种遗传风险因素与影像和行为数据相结合。总而言之，这些研究将有助于更好地了解 AD 遗传风险的神经基质和认知（记忆）后果。

项目成果

A Model For Teaching Advanced Neuroscience Methods: A Student-Run Seminar to Increase Practical Understanding and Confidence.

教授高级神经科学方法的模型：学生举办的研讨会，以增加实践理解和信心。

• 发表时间: 2016
• 期刊: Journal of undergraduate neuroscience education : JUNE : a publication of FUN, Faculty for Undergraduate Neuroscience
• 作者: Harrison,TheresaM;Ching,ChristopherRK;Andrews,AnneM
• 通讯作者: Andrews,AnneM