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

项目摘要/摘要 尽管40多年来一直没有找到治疗阿尔茨海默病(AD)的有效方法 研究强调，迫切需要新的战略来预防或推迟疾病的发生。建议数 调查旨在通过以下方式检查年龄相关认知能力下降的风险和弹性机制 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。 储备的概念被用来解释认知老化的巨大个体差异。 轨迹，对储量的潜在可改变决定因素有了初步的了解。然而， 基本问题仍然存在，例如，教育的影响，对认知的刺激 成年后的活动，或儿童早期对储备机制的丰富和认知能力的下降。 之前的调查受到一些限制的阻碍，包括缺乏：1) 儿童早期认知的前瞻性测量，需要解决反向因果关系的关键问题 困扰着这一领域；2)大时间窗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 样本。这项建议通过延长我们对普罗维登斯RI的持续研究来解决这些限制 美国合作围产期项目(CPP)的队列。最初的CPP涉及系统的数据收集 从怀孕到7岁，包括被认为影响早期生活的三个关键因素的测量 晚年的认知轨迹：儿童早期智商、家庭自尊和童年逆境。我们进行了一次 对该队列中720名年龄在35岁的成员进行综合认知评估。我们建议重新评估 这些参与者(现在快60岁了)需要进行详细的神经心理学检查 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 为血浆β-淀粉样蛋白(A-β)42/40比值和载脂蛋白E(ApoE)基因，并将经历结构性 和功能核磁共振，提供手术定义的大脑储备措施。最后，我们提出了一部小说 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：(1)确定教育程度的相对影响， 早年生活、成人生活方式因素对中老年认知水平的影响及衰退；(2)决定 特定的大脑储备机制对认知下降的相对贡献；以及(3)确定主要的 晚年大脑储备机制的决定因素。预计到2020年老年人口将翻一番 2050年将给美国医疗系统带来巨大的AD相关负担。通过提供新颖的见解 对于风险和弹性的机制，研究结果可能会导致新的战略来显著降低这一点 通过延缓认知衰退和阿尔茨海默病的发病而增加负担。

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.