ENIGMA World Aging Center

摘要 三分之一的老年人死于阿尔茨海默病（AD）或其他痴呆症-疾病花费了国家2590亿美元，到2050年将上升到1.1万亿美元（阿尔茨海默病协会，2017）。尽管这些疾病造成了巨大的个人和经济损失，但两个主要障碍阻碍了发现影响大脑衰老的关键生物机制的努力。首先，数据收集的成本意味着大多数国家计划在检测影响大脑老化的因素方面的能力有限。即使在N= 1，000+人的数据集中（例如，ADNI）-发现大脑老化调节剂的能力是有限的，可能不会在世界范围内推广。其次，由于再现性危机，我们并不总是知道一个发现是否会重复;如果不是，这是由于真正的群体异质性或方法问题。ENIGMA提供了一个协调的全球方法来解决这些问题。ENIGMA的世界老龄化中心是一个全球性的大脑老化研究，建立在我们庞大而富有成效的ENIGMA联盟-一个由45个国家的340个机构组成的全球网络。ENIGMA发表了有史以来规模最大的大脑遗传学研究（Nature 2017; Science 2020），以及5种主要精神疾病的最大神经影像学研究。ENIGMA的世界老龄化中心是一个协调一致的全球努力，汇集所有可用的数据，方法，专业知识和资本基础设施，以发现影响大脑老化的因素。我们的长期目标是确定大脑结构和功能衰退的个性化生物预测因子，并评估它们如何在全球范围内推广。我们有四个目标：目标1：谜-寿命。在20，000人中开发大脑和神经系统老化的寿命图表。我们将创建图表，显示MRI大脑如何测量2万名1-92岁的人在一生中的变化。我们将根据现有的MRI、DTI、rsFMRI数据计算一个复合大脑老化评分“Brain Aging”，该评分衡量一个人的年龄和性别的大脑偏离预期值的程度。目标2：ENIGMA-表观遗传学。将全基因组甲基化水平与10，000多人的大脑指标相关联，以发现大脑加速老化的表观遗传标记。我们在初步研究中发现了两个促进脑老化的表观遗传位点。我们将计算一个“表观遗传时钟”，并测试它是否能比简单的生物年龄更好地预测大脑指标。目标3：ENIGMA-可塑性。在全球> 37个纵向MRI队列中发现促进或减轻脑组织损失的基因组位点。目标4：谜-阿尔茨海默病（新目标）。荟萃分析APOE、AD多基因风险和加速萎缩的新风险评分对衰老和AD神经影像学生物标志物的作用，包括淀粉样蛋白和FDG PET。这些目标旨在通过协调一致的方法分析全球成像，表观遗传和临床数据。我们的目标是创建新的衰老“时钟”，并揭示基因组和表观基因组中脑衰老的靶向风险因素和修饰因子，测试它们如何以及何时改变AD生物标志物，并测试它们在全球范围内的普遍性。

ABSTRACT One in three seniors dies with Alzheimer’s disease (AD) or another dementia - diseases that cost the nation $259 billion, to rise to $1.1 trillion by 2050 (Alzheimer’s Association, 2017). Despite the vast personal and economic cost of these diseases, two major barriers stall efforts to discover key biological mechanisms that influence brain aging. First, the sheer cost of data collection means that most national initiatives have limited power to detect factors that affect brain aging. Even in datasets of N=1,000+ people (e.g., ADNI) – the power to discover modulators of brain aging is limited and may not generalize worldwide. Second, with the crisis of reproducibility, we do not always know if a finding will replicate; and if not, if this is due to true population heterogeneity or problems with methods. ENIGMA offers a coordinated global approach to solve these problems. ENIGMA’s World Aging Center is a global brain aging study that builds on our vast and highly productive ENIGMA consortium - a global network of 340 institutions in 45 countries. ENIGMA published the largest-ever genetic studies of the brain (Nature 2017; Science 2020), and the largest neuroimaging studies of 5 major psychiatric disorders. ENIGMA’s World Aging Center is a concerted global effort to pool all available data, methods, expertise and capital infrastructure to discover factors that affect brain aging. Our long-term goal is to identify personalized biological predictors of brain structural and functional decline and assess how they generalize globally. We have 4 aims: Aim 1: ENIGMA-Lifespan. Develop Lifespan Charts for Brain and Neural Tract Aging in 20,000 people. We will create charts showing how MRI brain measures change throughout life in 20,000 people, aged 1-92. We will compute a composite brain aging score, ‘Brain Age’, from available MRI, DTI, rsFMRI data, that measures how much the brain deviates from expected values, for a person’s age and sex. Aim 2: ENIGMA-Epigenetics. Relate genome-wide methylation levels to brain metrics in 10,000+ people, to discover epigenetic markers of accelerated brain aging. We discovered 2 epigenetic loci promoting brain aging in pilot studies. We will compute a “epigenetic clock” and test if it predicts brain metrics better than simple biological age. Aim 3: ENIGMA-Plasticity. Discover genomic loci that promote or mitigate brain tissue loss, in > 37 worldwide cohorts with longitudinal MRI. Aim 4: ENIGMA-Alzheimer’s Disease (New Aim). Meta-analyze the role of APOE, AD polygenic risk, and a new risk score for accelerated atrophy on neuroimaging biomarkers in aging and AD, including amyloid and FDG PET. These aims seek to analyze worldwide imaging, epigenetic, and clinical data with harmonized methods. We aim to create new aging “clocks” and reveal targetable risk factors and modifiers of brain aging in the genome and epigenome, test how and when they shift AD biomarkers, and test their generalizability worldwide.