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，占所有病例的50-75%。临床阿尔茨海默病首先影响情景记忆，但最终导致全身性痴呆，使患者严重认知受损，无法自理。明显的脑萎缩，特别是海马，以及正常结构和功能神经网络的破坏都与AD有关。这些变化极有可能难以逆转。因此，需要采取AD预防策略来保持大脑健康，防止导致大脑形态改变和认知能力下降的神经元丢失。任何特定疾病预防战略的一个关键组成部分是可靠地识别有患病风险的个体，以便将他们纳入对照临床试验。双胞胎研究表明，AD的遗传率为60- 80%，APOE基因型占遗传率变异的50%左右。因此，有很大一部分的遗传性是由其他基因来解释的。在全基因组关联研究和实验室实验中发现的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，这些基因在帮助识别可能患阿尔茨海默病的个体方面可能具有临床相关性。该建议建议使用非侵入性成像和认知测量来评估其潜在的临床应用。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标，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在认知健康的老年人队列中根据多种指标进行评估。根据文献支持的早期ad相关的大脑结构变化，包括海马体内和ad易感区域皮质变薄（如楔前叶、角回等），可以估计两年期间的衰退。认知衰退将通过创建每个时间点的记忆领域z分数来衡量（来自多个记忆性能测量，包括单词列表，故事和视觉单词对的回忆）。多基因风险评分可能比单独的APOE状态更敏感地预测这些指标的下降。为了确定阿尔茨海默病高危人群，本研究建议采用多学科方法，将多种遗传风险因素与影像学和行为数据相结合。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.