Mechanisms of Risk and Resilience to Age-Related Cognitive Decline: A 60-Year Prospective Prenatal Cohort

项目概要/摘要 尽管四十多年来一直没有找到任何有效的治疗阿尔茨海默病（AD）的方法， 研究强调，迫切需要采取新的战略来预防或推迟疾病的发作。拟议 一项研究旨在通过以下方式研究与年龄相关的认知能力下降的风险和恢复力机制： 利用认知神经科学的最新进展和独特的60年纵向产前队列。 储备的概念已经发展到解释认知老化的巨大个体差异 轨迹，初步了解储备的潜在可修改的决定因素。然而，在这方面， 例如，关于教育的影响，认知刺激， 活动在成年期，或幼儿期丰富储备机制和认知能力下降。 以前的调查受到一些限制的阻碍，包括缺乏： 幼儿认知的前瞻性措施，需要解决反向因果关系的关键问题 2）在一个大的时间窗口内成人认知能力下降的指标; 3）相关的测量 整个生命周期的社会行为因素;以及4）研究的经济和种族/民族多样性 样品本建议通过扩展我们对普罗维登斯RI的持续研究来解决这些局限性 美国围产期合作项目（CPP）。最初的CPP涉及系统的数据收集 从怀孕到7岁，包括三个关键的早期生活因素的措施，认为影响 认知轨迹在以后的生活：早期儿童智商，家庭SES，和童年逆境。我们进行了一项 在35岁时对该队列的720名成员进行全面的认知评估。我们建议重新评估 这些参与者（现在接近60岁）有一个详细的神经心理电池检查 在25年的时间里认知能力下降我们还将评估参与认知刺激活动的情况， 体力活动、职业复杂性、收入和健康状况。参与者将提供生物样本 血浆β-淀粉样蛋白（Aβ）42/40比值和载脂蛋白E（APOE）基因型，并将经历结构性 和功能性磁共振成像，提供可操作定义的大脑储备措施。最后，我们提出了一个新的 通过不同的大脑机制将寿命因素与认知结果联系起来的概念框架。 这一框架推动了我们的目标，即：（1）确定教育程度的相对影响， 早期生活方式和成人生活方式因素对认知水平的影响及中年晚期成人的下降;（2）确定 特定的脑储备机制对认知能力下降的相对贡献;（3）确定主要的 大脑储备机制的决定因素。预计到2010年老年人口将翻一番， 到2050年，美国医疗保健系统将面临巨大的广告相关负担。通过提供新颖的见解 研究结果可能会导致新的战略，以显着减少这一点， 通过延迟认知能力下降和阿尔茨海默病的发病来减轻负担。

PROJECT SUMMARY/ABSTRACT The failure to find any effective treatment for Alzheimer’s disease (AD) despite over four decades of research underscores the critical need for new strategies to prevent or delay disease onset. The proposed investigation aims to examine mechanisms of risk and resilience to age-related cognitive decline by leveraging recent advances in cognitive neuroscience and a unique 60-year longitudinal prenatal cohort. The concept of reserve has been developed to account for the large individual differences in cognitive aging trajectories, with nascent understanding of potential modifiable determinants of reserve. However, fundamental questions remain regarding, for instance, the impact of education, cognitively stimulating activities in adulthood, or early childhood enrichment on reserve mechanisms and cognitive decline. Previous investigations have been hampered by a number of limitations, including the lack of: 1) prospective measures of early childhood cognition, needed to address critical issues of reverse causation plaguing this field; 2) indices of adult cognitive decline over a large time window; 3) measures of relevant sociobehavioral factors across the entire lifespan; and 4) economic and racial/ethnic diversity of study samples. This proposal addresses these limitations by extending our continued study of the Providence RI cohort of the US Collaborative Perinatal Project (CPP). The original CPP involved systematic data collection from pregnancy through age 7 years, including measures of three key early life factors thought to influence cognitive trajectories in later life: early childhood IQ, family SES, and childhood adversity. We conducted a comprehensive cognitive assessment of 720 members of this cohort at age 35. We propose to reassess these participants (now approaching age 60) with a detailed neuropsychological battery to examine cognitive decline over a 25-year period. We will also assess engagement in cognitively stimulating activities, physical activity, occupational complexity, income, and health status. Participants will provide biosamples for plasma beta-amyloid (Aβ) 42/40 ratio and apolipoprotein E (APOE) genotype, and will undergo structural and functional MRI, providing operationally-defined brain measures of reserve. Finally, we propose a novel conceptual framework linking lifespan factors to cognitive outcomes through distinct brain mechanisms. This framework drives our aims which are: (1) Determine the relative influence of educational attainment, early life, and adult lifestyle factors on cognitive level and decline in late middle-aged adults; (2) Determine the relative contributions of specific brain reserve mechanisms to cognitive decline; and (3) Identify major determinants of brain reserve mechanisms in later life. A projected doubling of the elderly population by 2050 will place tremendous AD-related burden on the U.S. healthcare system. By providing novel insights into mechanisms of risk and resilience, findings may lead to new strategies to significantly reduce this burden by delaying cognitive decline and the onset of Alzheimer’s Disease.