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

摘要 血管健康已成为阿尔茨海默病和相关疾病最重要的决定因素之一 痴呆症。成人早期和中年心血管疾病(CVD)的危险因素和亚临床疾病 中年是认知衰退的重要驱动因素，这一时期很可能是影响晚年生活的关键时期 痴呆症风险。然而，很少有研究调查成年早期心血管疾病的风险暴露，包括 以及亚阈值水平是否会影响以后的生活认知。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地点冠状动脉风险开发的35年访问中 青年(CARDIA)研究。在基线时，CARDIA招募了5115名黑人和白人参与者(平均年龄 24)被仔细跟踪了30年，并在访问25年和30年时进行了认知测试。认知 35岁时的评估将使我们能够在关键时刻确定10年认知变化(平均年龄为50至60岁) 认知能力下降开始分化并可能影响晚年痴呆风险的时间点。我们的具体目标 是：1)使用生命过程方法，确定10年中年认知的独立关联 心血管疾病危险因素，包括体重，随着时间、水平(阈值以下和阈值以下)和趋势而下降 指数、血压和空腹血糖，从成年早期到中年，评估年龄超过35岁；2)确定 随着时间的推移，10年中年认知下降与新的亚临床心血管疾病标记物的相关性包括 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 风险因素和亚临床心血管疾病标记物与中年脑老化指数相关，由 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 对近700名中年CARDIA参与者进行了调查；探索性)，以评估10- 并确定这种差异在多大程度上是由心血管疾病风险负担解释的。 在强劲的初步数据指导下，我们的主要假设是心血管疾病风险因素很早就开始发挥影响。 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 这件事的驱动因素。此外，我们假设亚临床心血管指标(特别是心功能和 动脉粥样硬化)与中年认知能力下降和大脑加速老化有关。没有其他人了 美国的一项研究拥有关于一系列早期成人心血管疾病风险因素的全面数据，这些因素可能 影响认知老化。作为一支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心血管疾病风险因素和亚临床疾病的基本独特的纵向数据， 我们有机会研究这些生命过程中的暴露与认知能力下降之间的联系 以及中年的大脑健康。在生命周期早期识别痴呆症的危险因素可能会导致干预 帮助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.