Cardiometabolic Risk Factors and Risk of Dementia

项目摘要/摘要 痴呆症的原因尚不清楚，但它被认为是一种多因素疾病，由 遗传因素和环境因素的相互作用，导致其发生和表达。 全基因组关联研究和基于人群的研究证实，载脂蛋白E的ε4等位基因是 痴呆症最强的遗传风险因素。然而，APOEε4被认为对 50%的痴呆症风险，这表明环境因素在老年人痴呆症的发展中起作用 先天遗传的。鉴于缺乏足够的痴呆症治疗选择，预防战略 或推迟疾病的发病是迫切需要的。在痴呆症的潜在可改变决定因素中， 适当控制心脏代谢危险因素[体重指数(BMI)、收缩和舒张压 压力、糖尿病和高胆固醇血症]可能是减少痴呆症发病率的主要策略。 然而，晚年的心脏代谢危险因素与痴呆症的关系并不一致 增加和降低患痴呆症的风险。研究结果中不一致的原因尚不清楚， 也许部分原因不仅是因为心脏代谢评估之间的随访时间不同 危险因素和痴呆症的发病(反向因果偏倚)，也是人群异质性。先前的研究已经 使用一次性基线心脏代谢危险因素测量或纵向测量 仅以平均水平变化(即，总体平均轨迹)为目标，只有一个轨迹，而 忽视种群的异质性。我们建议使用嵌套式病例对照设计，以小组为基础 轨迹分析方法用于分析大型、多点、纵向老化和痴呆数据集--一致性 数据集(UDS)由国家阿尔茨海默病协调中心(NACC)提供。目标1)：将嵌套的 以病例对照的方法确定心脏代谢危险因素在诊断前的不同轨迹 痴呆组(最大15岁)和匹配对照组使用基于群体的轨迹模型，并检查 心脏代谢危险因素的不同轨迹、载脂蛋白E基因及其相互作用对风险的影响 使用嵌套在UDS队列中的匹配病例对照亚样进行痴呆症的研究。目标2)：调查相反的情况 目的1)心脏代谢危险因素与痴呆症之间关系的因果偏差。至 探讨心脏代谢危险因素的运动轨迹及其与载脂蛋白E基因的相互作用 患痴呆症的风险因种族、性别、基线年龄和阿尔茨海默病(AD)亚型而异。

Project Summary/Abstract The cause of dementia is unknown, but it is considered to be a multifactorial disease, resulting from the interaction of both genetic and environmental factors, which contribute to its occurrence and expression. Genome­wide association studies and population­based studies have confirmed that the ε4 allele of APOE is the strongest genetic risk factor for dementia. However, APOE ε4 is thought to be responsible for less than 50% of dementia risk, suggesting that environmental factors contribute to development of dementia in the genetically predisposed. Given the absence of sufficient treatment options for dementia, strategies to prevent or delay the disease onset are urgently needed. Among potentially modifiable determinants of dementia, appropriate control of cardiometabolic risk factors [Body Mass Index (BMI), systolic and diastolic blood pressure, diabetes and hypercholesterolemia] could be a primary strategy to reduce the incidence of dementia. However, cardiometabolic risk factors in later life have been inconsistently associated with dementia with both increased and decreased risk for dementia. The reasons for this discordance in findings are unclear and perhaps partially due to not only the differing lengths of follow­up between the assessments of cardiometabolic risk factors and dementia onset (reverse causation bias), but also population heterogeneity. Prior studies have used either one­time baseline cardiometabolic risk factor measurements or longitudinal measurements targeting only on mean­level changes (i.e., population average trajectory) with only one trajectory while ignoring population heterogeneity. We propose to use a nested case­control design with group­based trajectory analysis approach to analyze a large, multisite, longitudinal aging and dementia dataset—Uniform Data Set (UDS) provided by the National Alzheimer’s Coordinating Center (NACC). Aim 1): To apply a nested case­control approach to identify distinct trajectories of cardiometabolic risk factors preceding the diagnosis of dementia (up to 15 years) and matched control group using group­based trajectory model, and to examine the effects of distinct trajectories of cardiometabolic risk factors, APOE genotype, and their interaction on the risk of dementia using matched case­control subsamples nested in UDS cohort. Aim 2): To investigate the reverse causation bias for the associations between cardiometabolic risk factors and dementia in aim 1. Aim 3). To explore whether the trajectories of cardiometabolic risk factors and their interaction with APOE genotype on the risk of dementia differ by race, sex, baseline age, and Alzheimer’s disease (AD) subtype.