The VETSA Longitudinal Twin Study of Cognition and Aging (VETSA 4)

项目摘要/摘要 阿尔茨海默病(AD)是美国成本最高、负担最重的疾病。它对公共卫生的影响将 在接下来的十年里，只有随着65-75岁年龄段的增加才能增长。公元20年或更长时间的公元进程 在痴呆症发作之前。在早期阶段(例如，轻度认知障碍([MCI]))识别个体 估计会带来巨大的节省。因此，美国国立卫生研究院和阿尔茨海默氏症协会达成共识声明 强调及早识别。就像心血管疾病一样，关注中年对于早期是至关重要的 识别认知功能减退、临床前AD和MCI的风险。尽管AD的进展旷日持久 病理方面，人们对其时间进程及其与中年认知的关系知之甚少。要解决这个问题 关键的知识缺口，我们建议在越南时代的双胞胎老龄化研究中收集第四波数据 (Vetsa)。Vetsa提供了整个中年变化的详细特征。随着第四波的到来，维萨将 在我们的社区居住样本中涵盖了18年的时间。Vetsa从几乎所有的受试者开始 50s，因此我们可以跟踪从正常认知到MCI/AD以及从正常到异常生物标记物状态的变化。我们 重点关注4组指标，它们可以比大多数研究更早地提高识别高危个人的能力： 1)广泛的认知测试；2)β-淀粉样蛋白(A-β)、tau和神经丝光的血浆AD生物标志物 (NFL)；3)多基因风险评分；以及4)认知过程的新评估。几乎所有的受试者都会有 β-在Vetsa 1。Vetsa 4的平均年龄将为74岁，荟萃分析表明，30%的非Vetsa 75岁的痴呆症成年人是Aβ+。因此，利用来自前几波的数据，时机是捕获的理想时机 向疾病状态的转变。我们使用淀粉样蛋白-tau-神经变性(ATN)生物标记物分类 系统，并检查拟议的AD连续体的A→T→N阶段。自然，大多数研究都将重点放在 ATN生物标志物作为预测指标，但在到达之前识别有风险的人将是非常有利的 病理性Aβ水平。因此，Aim1将检查血浆ATN生物标记物的轨迹以及预测 ATN生物标志物的聚集和异常。我们有来自Vetsa 1和3的生物标记物数据，并将执行 对Vetsa 4数据进行分析。目的2建立认知功能衰退的风险和保护因素模型，生物标记物 轨迹，并使用可以检验因果关系的遗传信息分析进展到MCI。有4次 积分，我们将使用双胞胎和多基因风险得分数据的组合，以及我们广泛的健康/医疗和 心理社会数据，以阐明导致认知能力减退加速的因素。在目标3中，我们评估2 新的早期风险指标：a)扩展我们关于瞳孔扩大的工作，作为之前认知努力的一种衡量标准 认知能力下降；以及b)评估视觉短期记忆绑定，这是一项测试的早期指标 主要是在家族性AD家族中。为了增加对下降的检测，Aim 4增加了电话/邮寄评估 资助期已过半。波4的N=1000。Vetsa的独特功能使其成为最有前途的 促进早期识别知识的资源，有可能对公共卫生产生深远影响。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most costly and burdensome disease in the U.S. Its public health impact will only grow with the increase of 65-75 year olds in the next decade. The AD process begins 2 or more decades before dementia onset. Identifying individuals during early stages (e.g., mild cognitive impairment ([MCI]) is estimated to result in massive savings. Thus, NIH and Alzheimer's Association consensus statements emphasize early identification. Like cardiovascular disease, focusing on middle age is crucial for earlier identification of risk for cognitive decline, preclinical AD, and MCI. Despite this protracted progression of AD pathology, little is known about its temporal course and relation to cognition in middle age. To address this critical knowledge gap, we propose to collect a fourth wave of data in the Vietnam Era Twin Study of Aging (VETSA). VETSA provides detailed characterization of change throughout midlife. With wave 4, VETSA will cover an 18-year period in our community-dwelling sample. VETSA began with virtually all subjects in their 50s, so we can track shifts from normal cognition to MCI/AD and normal to abnormal biomarker status. We focus on 4 sets of indicators that improve the ability to identify at-risk individuals earlier than in most studies: 1) extensive cognitive testing; 2) plasma AD biomarkers for beta-amyloid (Aβ), tau, and neurofilament light (NfL); 3) polygenic risk scores; and 4) novel assessments of cognitive processes. Almost all subjects will have been Aβ- at VETSA 1. Average age at VETSA 4 will be 74, and a meta-analysis indicates that >30% of non- demented adults at age 75 are Aβ+. Thus, leveraging data from previous waves, the timing is ideal to capture the transition to disease states. We utilize the amyloid-tau-neurodegeneration (ATN) biomarker classification system and examine the proposed A→T→N staging of the AD continuum. Naturally, most research focuses on ATN biomarkers as predictors, but it would be highly advantageous to identify people at risk before reaching pathological Aβ levels. Thus, Aim1 will examine plasma ATN biomarker trajectories as well as predictors of ATN biomarker accumulation and abnormality. We have biomarker data from VETSA 1 and 3, and will perform assays on VETSA 4 data. Aim 2 models risk and protective factors for cognitive decline, biomarker trajectories, and progression to MCI using genetically-informative analyses that can test causality. With 4 time points, we will use our combination of twin and polygenic risk score data and our extensive health/medical and psychosocial data to elucidate factors accounting for accelerated cognitive decline. In Aim 3, we evaluate 2 novel early risk indicators by: a) extending our work on pupil dilation as a measure of cognitive effort before cognitive performance declines; and b) assessing visual short-term memory binding, an early indicator tested primarily in familial AD families. To increase detection of decline, Aim 4 adds telephone/mailed assessments partway in the funding period. Wave 4 will have N=1000. VETSA's unique features make it a most promising resource for advancing knowledge about early identification, with potential for a profound public health impact.