The Role of Executive Functions in Cognitive Aging and Risk for Mild Cognitive Impairment

项目总结 改善阿尔茨海默病(AD)治疗的努力开始集中在早期识别上 因为在轻度认知障碍(MCI)阶段诊断个体可以提高患者的质量 并大大减少这种疾病对经济的影响。中年的认知评估提供了 理想的早期预测或筛查，因为它们是低成本和非侵入性的工具。尽管具有预测性 对MCI和AD的研究一般集中在情景记忆，执行功能(EFS)是相当重要的 之所以重要，是因为它们控制和整合多个认知过程，也因为它们的表现 而相关的大脑区域在中年时是最先衰退的。事实上，有突出的 在MCI和AD中EFS的缺陷，但很少有研究纵向检查这些联系。我们建议 在发展为MCI和AD的过程中，EF缺陷可能比记忆缺陷出现得更早(或更早)。我们 将评估EFS和记忆力作为预测中年MCI的指标，并与另一项有希望的早期评估相结合 指标--AD多基因评分(目标1)。遗传风险评分在前瞻性研究中可能变得非常有用 因为基因分型程序也是非侵入性的，可以在生活中的任何时候进行。具体来说，我们将 研究认知测量是否能更有力地预测阿尔茨海默病遗传风险高的个体的MCI 得分。我们还将研究其他早期生活因素(认知储备)是如何阐明这种联系的。 中年EFS、脑白质和AD遗传风险之间的关系(目标2)。 我们将检查越南时期双胞胎老龄化研究的数据，该研究跟踪了大样本的男性双胞胎 中年后期跨越3个时点(平均年龄56、62、67岁，每波N~1200)。双胞胎已完成 对所有波的EFS进行广泛评估(包括多项反应抑制措施、任务集 转换、工作记忆和语言流畅性)以及其他认知能力的多种测量 (包括记忆力)、健康和心血管因素。成人早期一般认知能力(N=1552；我们的 认知储备的代用品)和基因分型(N=1162)适用于大多数个体。白质数据是 也适用于许多受试者(每波N~350至400)。综合认知测评在中国的应用 Vetsa允许在潜在变量的水平上检查EFS和记忆，增加了能力和 结论的概括性。此外，样本的遗传信息性(即双胞胎和直系 基因分型)，允许将EFS和白质之间的关联分解为遗传和 环境影响，以及AD遗传风险分数在这些关联中的作用的检查。 这一奖项将提供一个理想的机会来促进我们对EFS和认知变化的理解 在一个丰富的数据集中横跨中年。由于所有研究都涉及对现有数据的二次分析，因此 将有充裕的时间来实现这项提案的研究目标。这项工作也将对发展起到推动作用 独立资助的项目(例如，R01)，旨在改善对MCI和AD风险的早期识别。

PROJECT SUMMARY Efforts to improve treatment of Alzheimer’s disease (AD) are beginning to focus on early identification because diagnosing individuals in the mild cognitive impairment (MCI) stage could improve patient quality of life and substantially reduce the financial impact of the disease. Cognitive assessments in middle age provide ideal early predictors or screeners because they are low cost and non- invasive tools. Although predictive studies of MCI and AD generally focus on episodic memory, executive functions (EFs) are of substantial importance because they control and integrate multiple cognitive processes, and because their performance and associated brain regions are some of the first to decline in middle age. Indeed, there are prominent deficits in EFs in MCI and AD, but few studies have examined these associations longitudinally. We propose that EF deficits can appear as early (or earlier) than memory deficits in the progression to MCI and AD. We will evaluate EFs and memory as predictors of MCI in middle age in combination with another promising early indicator – AD polygenic scores (Aim 1). Genetic risk scores may become highly useful in prospective studies because genotyping procedures are also non-invasive and can be done anytime in life. Specifically, we will examine whether cognitive measures predict MCI more strongly in individuals with high AD genetic risk scores. We will also examine how other early life factors (cognitive reserve) elucidate the associations between EFs, white matter, and AD genetic risk in midlife (Aim 2). We will examine data from the Vietnam Era Twin Study of Aging, which follows a large sample of male twins across 3 time-points in late middle age (mean age 56, 62, and 67; N~1200 at each wave). Twins completed extensive assessment of EFs at all waves (including multiple measures of response inhibition, task-set shifting, working memory, and verbal fluency) as well as multiple measures of other cognitive abilities (including memory), health, and cardiovascular factors. Early adult general cognitive ability (N=1552; our proxy for cognitive reserve) and genotyping (N=1162) are available for most individuals. White matter data are also available for many subjects (N~ 350 to 400 at each wave). The comprehensive cognitive assessment in VETSA allows for the examination of EFs and memory at the level of latent variables, increasing power and generalizability of findings. Moreover, the genetically-informative nature of the sample (i.e., twins and direct genotyping), allows for the decomposition of associations between EFs and white matter into genetic and environmental influences, and examination of the role of AD genetic risk scores in these associations. This award will provide an ideal opportunity to advance our understanding of EFs and cognitive changes across middle age in a rich dataset. Because all research involves secondary analyses of existing data, there will be ample time to achieve the research aims of this proposal. This work will also lead to the development of independently funded projects (e.g., R01) aimed at improving early identification of MCI and AD risk.