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

描述(申请人提供)：阿尔茨海默病(AD)是最常见的痴呆症形式，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，无法照顾自己。显著的脑萎缩，特别是在海马区，以及正常的结构和功能神经网络的破坏都与AD有关。很可能，这些变化极难逆转。因此，AD的预防策略是必要的，以保护大脑健康，防止神经元丢失，从而导致大脑的形态变化和认知能力下降。任何针对疾病的预防战略的一个关键组成部分是可靠地确定哪些人有罹患这种疾病的风险，以便他们可以参加受控的临床试验。双生子研究表明，AD的遗传度在60-80之间，APOE基因可解释约50%的遗传度变异。因此，遗传性有很大一部分是由其他基因解释的。全基因组关联研究和台架实验确定的AD危险基因是潜在的候选基因，为研究AD发病的分子基础提供了可能的靶点。此外，这些基因在帮助识别有可能发展为AD的个体方面可能具有临床相关性。这项建议建议使用非侵入性成像和认知测量来评估这一潜在的临床应用。其目的是通过根据载脂蛋白E状态、AD家族史和其他AD风险基因创建多基因风险指数来确定非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认知健康的老年人队列中的多种衰退指标进行评估。两年期间的下降将基于文献支持的与AD相关的大脑结构的早期变化来估计，包括海马体内和皮质带中易患AD的区域(例如，楔前叶、角回等)的皮质变薄。认知衰退将通过为每个时间点创建记忆领域Z分数(来自多个记忆性能测量，包括对单词列表、故事和视觉单词对的回忆)来衡量。与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指标。为了确定阿尔茨海默病风险最高的个体，这项建议建议采用一种多学科方法，将多种遗传风险因素与成像和行为数据相结合。综上所述，这些研究将更好地了解阿尔茨海默病的神经基础和遗传风险的认知(记忆)后果。

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.