Cardiometabolic Risk Factors and Risk of Dementia

项目总结/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 遗传和环境因素的相互作用，这有助于其发生和表达。 全基因组关联研究和基于群体遗传学的研究已经证实，APOE的ε4等位基因是 痴呆症最强的遗传风险因素。然而，APOE ε4被认为是负责不到 50%的痴呆症风险，这表明环境因素有助于痴呆症的发展， 有遗传倾向鉴于缺乏足够的痴呆症治疗选择，预防痴呆症的战略 或延缓疾病的发生是迫切需要的。在痴呆症的潜在可改变的决定因素中， 适当控制心脏代谢风险因素[体重指数（BMI）、收缩压和舒张压 高血压、糖尿病和高胆固醇血症]可能是降低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相关性并不一致， 增加和降低痴呆症的风险。研究结果不一致的原因尚不清楚， 可能部分原因不仅是心脏代谢评估之间的随访时间不同， 风险因素和痴呆发作（反向因果偏差），而且人口异质性。先前的研究 使用一次基线心脏代谢危险因素测量或纵向测量 仅针对平均水平变化（即，人口平均轨迹），只有一个轨迹， 忽略了种群的异质性。我们建议使用一个嵌套的情况下，控制设计与组的基础上， 轨迹分析方法来分析一个大的，多地点，纵向老化和痴呆症的统一 数据集（UDS）由国家阿尔茨海默病协调中心（NACC）提供。目标1）：应用嵌套的 病例对照方法，以确定诊断前心脏代谢危险因素的不同轨迹 痴呆（15岁以下）和匹配的对照组，使用基于组间关系的轨迹模型，并检查 心脏代谢危险因素、APOE基因型的不同轨迹及其相互作用对风险的影响 使用UDS队列中匹配的病例对照子样本进行痴呆的研究。目标2：研究反向 aim 1中心血管代谢危险因素与痴呆之间关联的因果偏倚。目标3）。到 探讨心脏代谢危险因素的轨迹及其与APOE基因型的相互作用， 痴呆风险因种族、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.