Lifecourse CVD Risk and Midlife Cognitive Trajectories and Brain Aging: Implications for Alzheimer's and Dementia Prevention

摘要 血管健康已经成为阿尔茨海默病和相关疾病的最重要的决定因素之一。 痴呆症早期成人和中年心血管疾病（CVD）的危险因素和亚临床疾病可能是 中年认知能力下降的重要驱动因素，这一时期很可能是影响晚年生活的关键 痴呆风险然而，很少有研究调查成年早期CVD风险暴露，包括 暴露以及阈下水平是否影响晚年认知。为了实现这些目标，我们建议， 将认知测试添加到正在进行的多部位冠状动脉风险发展的35年访视中， 年轻人（CARDIA）研究。基线时，CARDIA招募了5，115名黑人和白色参与者（平均年龄 24)他们已经被仔细跟踪了30年，并在第25年和第30年进行了认知测试。认知 35岁时的评估将使我们能够在关键时刻确定10年的认知变化（平均年龄50至60岁） 当认知能力下降开始分化并可能影响老年痴呆症风险时。我们的具体目标 1）使用生命过程方法，确定10年中年认知的独立关联， CVD风险因素（包括体重）随时间、水平（阈下和阈下）和趋势下降 指数、血压和空腹血糖，从早期成人到中年评估35年; 2）确定 随着时间的推移，10年中年认知能力下降与新的亚临床CVD标志物的相关性，包括 颈动脉内膜厚度、冠状动脉钙化和心功能; 3）确定是否有心血管疾病 危险因素和亚临床CVD标志物与中年脑老化指数相关， 机器学习神经成像模式分析在脑MRI和扩散张量成像数据中的应用 在近700名中年CARDIA参与者中获得;探索性）为了评估10- 15岁年龄组中的黑人/白色差异， 年认知能力下降，并确定这种差异在多大程度上是由CVD风险负担解释的。 在强有力的初步数据的指导下，我们的主要假设是，CVD危险因素开始发挥影响， 作为生命的第三个十年，亚阈值水平（如收缩压≥120 mm）是重要的 司机对此此外，我们假设亚临床CVD指标（特别是心功能和 动脉粥样硬化）与中年认知能力的更大下降和大脑老化的加速有关。没有其他 美国的一项研究对一系列早期成人CVD风险因素提供了如此全面的数据， 影响认知老化。作为一个经验丰富的多学科团队，使用创新的统计方法， 分析关于早期成人和中年CVD风险因素和亚临床疾病的基本独特的纵向数据， 我们有机会调查这些生命过程中的暴露与认知能力下降的关系 和大脑健康之间的关系在生命过程的早期识别痴呆风险因素可能会导致干预措施， 有助于保持健康的大脑老化，防止痴呆症的发生。

ABSTRACT Vascular health has emerged as one of the most important determinants of Alzheimer's disease and related dementias. Early adult and midlife cardiovascular disease (CVD) risk factors and subclinical disease may be important drivers of cognitive decline in midlife, a period that most likely is critical for influencing later life dementia risk. Yet, few studies have investigated early adulthood CVD risk exposures, including timing of exposure and whether subthreshold levels impact later life cognition. To accomplish these goals, we propose, to add cognitive testing to the Year 35 visit of the ongoing multisite Coronary Artery Risk Development in Young Adults (CARDIA) study. At baseline, CARDIA enrolled 5,115 black and white participants (mean age 24) who have been carefully followed for 30 years and had cognitive testing at visit years 25 and 30. Cognitive evaluation at Year 35 will allow us to determine 10-year cognitive change (mean age 50 to 60) at a critical time point when cognitive decline starts to diverge and potentially impacts late-life dementia risk. Our specific aims are: 1) To determine, using a life-course approach, the independent associations of 10-year midlife cognitive decline with timing, level (both subthreshold and threshold) and trend in CVD risk factors including body mass index, blood pressure, and fasting glucose, assessed over 35 years from early adult to midlife; 2) To determine the association of 10-year midlife cognitive decline with novel subclinical CVD markers over time including carotid artery intima thickness, coronary artery calcification and cardiac function; 3) To determine whether CVD risk factors and subclinical CVD markers are associated with brain aging indices in midlife, derived by the application of machine-learning neuroimaging pattern analysis to brain MRI and diffusion tensor imaging data obtained on nearly 700 CARDIA participants at midlife; Exploratory) To assess black/white disparities in 10- year cognitive decline and determine the extent to which such disparities are explained by burden of CVD risk. Guided by strong preliminary data, our main hypothesis is that CVD risk factors begin to exert influence as early as the third decade of life and that subthreshold levels (eg systolic blood pressure ≥120 mm) are important drivers for this. In addition, we hypothesize that subclinical CVD measures (especially cardiac function and atherosclerosis) are associated with greater decline in midlife cognition and accelerated brain aging. No other study in the US has such comprehensive data on a wide array of early adult CVD risk factors that may influence cognitive aging. As an experienced multidisciplinary team using innovative statistical methods to analyze essentially unique longitudinal data on early adult and midlife CVD risk factors and subclinical disease, we have the opportunity to investigate the associations of these life-course exposures with cognitive decline and brain health in midlife. Identifying dementia risk factors early in the life-course may lead to interventions to help maintain healthy brain aging and prevent the onset of dementia.