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

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆形式，占所有病例的50-75%。临床AD首先影响情景记忆，但最终导致全面痴呆，使患者严重认知受损，无法照顾自己。显著的脑萎缩，特别是海马，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AD预防策略来保护大脑健康并防止导致大脑形态学变化和认知能力下降的神经元损失。 任何针对特定疾病的预防战略的一个关键组成部分是可靠地识别有发展疾病风险的个人，以便他们可以参加对照临床试验。双生子研究表明，AD的遗传度为60-80，APOE基因型约占遗传度变异的50%。因此，有很大一部分遗传性是由其他基因解释的。在全基因组关联研究和台架实验中发现的AD风险基因是潜在的候选基因，为研究AD发病机制的分子基础提供了可能的靶点。此外，这些基因可能在帮助识别可能发展为AD的个体方面具有临床相关性。该提案建议使用非侵入性成像和认知测量来评估这种潜在的临床用途。 目的是通过建立基于APOE状态、AD家族史和其他AD风险基因的多基因风险指数，确定非APOE AD风险基因是否具有额外的临床预测价值。这些评分的预测能力将根据认知健康老年人队列中的多个下降指标进行评估。将根据文献中支持的早期AD相关脑结构变化估计两年期间的下降，包括海马内的皮质变薄和皮质带的AD易感区域（例如，楔前叶、角回等）。将通过创建每个时间点的记忆域Z评分（来自多个记忆性能指标，包括单词列表、故事和视觉单词对的回忆）来测量认知下降。多基因风险评分可能是一个更敏感的预测指标下降比APOE状态单独。 为了识别AD风险最高的个体，该提案建议采用多学科方法，将多种遗传风险因素与成像和行为数据相结合。总之，这些研究将提供更好的理解AD遗传风险的神经基质和认知（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.