JPND BRain Imaging, cognition, Dementia and next generation GEnomics

为痴呆症和阿尔茨海默病(AD)建立有效的预防战略是未来几年的主要卫生优先事项。一个重要的障碍是导致AD的病理过程在临床诊断之前很多年就开始了，因此应该很早就开始有效的预防。这需要识别普通人群中患痴呆症的高风险个人，并探索痴呆症发生前大脑结构性变化背后的分子路径，这是确定新的相关药物靶点的关键步骤。为了解决这些重要的问题，我们建议探索大脑老化的定量MRI标记物的遗传和表观遗传决定因素，这些标记物是痴呆/AD风险的强大预测因子，并检查这些标记物在基于人群的环境中的临床意义。利用在欧洲最大的基于人群的队列研究中收集的大量信息和神经成像数据，我们将首先搜索与脑老化的现有和新的MRI标记相关的遗传变异，特别是罕见的变异，使用不可知和候选基因座方法(通过全基因组关联研究[GWAS]确定为与AD相关的基因座或与脑老化的MRI标记相关的基因座)。与GWAS信号相比，罕见的变异可能会导致因果变异的发现，而且几乎没有人研究过与结构MRI标记相关的变异。其次，我们将采取原创的终生观点，通过检查从年轻成年到老年的不同年龄段的样本，其中许多样本进行了重复的核磁共振和血液采样。事实上，越来越多的证据表明，早期生活因素在迟发性神经退行性疾病的发生中发挥着重要作用。我们提出了一种创新的探索，使用一种新的亚硫酸氢盐测序技术，对与脑结构改变相关的甲基化的寿命变化进行探索，以帮助识别功能和疾病相关的变体。我们还将研究血管危险因素和社会经济地位对脑老化的遗传/表观遗传决定因素的修正作用。第三，我们将利用所有研究中复杂的认知测试和前瞻性痴呆症监测，通过检查它们与认知表现、认知衰退和痴呆症/AD风险的关系，来探索我们确定的遗传和表观遗传学标记的临床意义。

Establishing efficient prevention strategies for dementia and Alzheimer disease (AD) is a major health priority for the coming years. An important hurdle is that pathological processes leading to AD begin many years before clinical diagnosis, hence efficient prevention should be initiated very early. This requires identifying individuals in the general population who are at high risk of developing dementia and exploring the molecular pathways underlying the structural brain alterations that precede the occurrence of dementia, an essential step for identifying novel relevant drug targets. To tackle these important questions we propose to explore the genetic and epigenetic determinants of quantitative MRI-markers of brain aging that are powerful predictors of dementia/AD risk, and to examine the clinical significance of the markers in a population-based setting. Leveraging the extensive information collected within the largest European population-based cohort studies with neuroimaging data, we will first search for genetic variants associated with established and novel MRI-markers of brain aging, focusing particularly on rare variants, using both an agnostic and candidate locus approach (loci identified through genome-wide association studies [GWAS] as associated AD or with MRI-markers of brain aging). In contrast with GWAS signals, rare variants may lead to the discovery of causal variants, and have hardly been explored in association with structural MRI-markers. Second, we will take an original lifetime perspective, through examination of samples in various age categories spanning from young adulthood to older age, many of which with repeated MRI and blood sampling. Indeed, there is increasing evidence that early-life factors play an important role in the occurrence of late-onset neurodegenerative diseases. We propose an innovative exploration of lifetime changes in methylation associated with structural brain alterations using a novel bisulfite sequencing technology, to help identify functional and disease relevant variants. We will also study the modifying effect of vascular risk factors and socio-economic status on genetic/epigenetic determinants of brain aging. Third, we will explore the clinical significance of genetic and epigenetic markers we identify by examining their association with cognitive performance, cognitive decline and risk of dementia/AD, capitalizing on the elaborate cognitive testing and prospective dementia surveillance available in all studies.