The predicative values of vascular and metabolic disorders for risk of incident mild cognitive impairment and dementia

项目摘要/摘要 痴呆症是一种在一定程度上影响思维、判断、记忆和其他认知领域的疾病 这会干扰日常活动的进行。阿尔茨海默病(AD)是最常见的 痴呆症。2021年，美国估计有620万65岁的成年人患有痴呆症，这一数字是 预计到2060年将达到近1400万人。女性患阿尔茨海默病的风险明显高于男性。关于 三分之二的痴呆症患者是女性。轻度认知障碍(MCI)，代表早期 疾病的阶段，指的是患者经历短期记忆下降的状态，或 其他认知领域，但在日常功能上没有明显损害。尽管主要是痴呆症 影响老年人，它不是正常衰老的一部分。鉴于在MCI早期阶段采取预防措施 延缓疾病的发展。早期发现MCI是非常重要的。 有症状的阶段。几项研究发现，血管、代谢紊乱和炎症 与MCI、AD和AD相关痴呆(AD/ADRD)的风险相关。然而，研究差距仍然存在：(1) 从之前的研究中观察到了不一致的结果。(2)大规模以人口为基础的研究 AD和痴呆的风险是有限的。(3)虽然已知MCI的风险与痴呆症有关 随着风险暴露的变化，很少有研究测试时变暴露与风险之间的联系 关于结果的。在应用程序中，我们旨在通过使用严格的研究设计来测试 血管和代谢紊乱、炎症以及遗传因素对糖尿病风险的预测价值 事件MCI和痴呆症，然后开发一个新的累积(组合)预测指数。我们有两个 明确的目标。目的1：研究血管、代谢和炎症生物标记物之间的关系 老年妇女有发生MCI和痴呆症的风险。假设：血管、代谢和 炎性生物标记物，具有随时间变化的措施，显著预测发生MCI和 65-79岁女性中的痴呆症，这些关联被载脂蛋白E基因(ε4与另一种 等位基因)。目标2：开发一种支持机器学习(ML)的算法来预测谁是 有发生MCI和痴呆症的高风险。假设：一种新颖的高级风险预测模型(例如， 集成了多个风险因素和关键因素的预测值的多维风险模型 协变量，将提高对事件MCI和痴呆风险的预测程度。 这项拟议的研究解决了人口老龄化面临的重大公共卫生挑战。这个 建议的研究是创新的，其特点是(1)侧重于老年妇女的性别研究；(2) 处理可能对研究结果有显著预测作用的时变风险因素。(3) 我们将测试APOE是否对研究之间的关联有潜在的修饰作用 曝光率和结果。这项研究在科学上有希望的方面是它能够 使用独特的大规模人群数据测试MCI和痴呆症的自然发展 妇女健康倡议记忆研究。研究结果将会透过 发表在高影响力期刊上的科学会议和研究文章，并为 预防和控制MCI和痴呆。

Project Summary/Abstract Dementia is a condition affecting thinking, judgment, memory and other cognitive domains to the degree that interferes with performing everyday activities. Alzheimer’s disease (AD) is the most common type of dementia. In 2021, an estimated 6.2 million adults in the US aged ≥65 have dementia, and the number is projected to be nearly 14 million by 2060. Women a have significantly higher risk of AD than men. About two thirds of patients with dementia are women. Mild cognitive impairment (MCI), representing the early stage of the disease, refers to a state in which the patient experiences a decline in short-term memory, or other cognitive domain, but with no significant impairment in everyday functioning. Though dementia mostly affects older adults, it is not a part of normal aging. Given that taking prevention at the early stage of MCI delays the development of the disease. It is of tremendous important to detect MCI during the early pre- symptomatic stage. Several studies observed that vascular, metabolic disorders, and inflammation are associated with risk of MCI, AD and AD related dementia (AD/ADRD). However, research gaps remain: (1) inconsistent findings were observed from the previous studies. (2) Large-scale population-based studies for AD and dementia risk are limited. (3) Although it is known that the risk of MCI and dementia are associated with changes in risk exposures, few studies tested the association between time-varying exposures and risk of outcomes. In the application, we aim at filling these gaps by using a rigorous study design to test the predictive values of vascular and metabolic disorders, inflammation, as well as genetic factors for the risk of incident MCI and dementia, and then develop a novel cumulative (combined) prediction index. We have 2 specific aims. Aim 1: To examine the association of vascular, metabolic and inflammatory biomarkers with risk of incident MCI and dementia in older women. Hypothesis: vascular, metabolic and inflammatory biomarkers, with time-varying measures significantly predict the risk of incident MCI and dementia in women aged 65-79, and these associations are modified by APOE gene (ε4 versus the other alleles). Aim 2: To develop a machine learning (ML)-enabled algorithm to predict individuals who are at high risk of incident MCI and dementia. Hypothesis: A novel and advanced risk prediction model (e.g., a multi-dimensional risk model using ML) that integrates predictive values of multiple risk factors and key covariates, will enhance the degree of the prediction for the risk of incident MCI and dementia. The proposed study addresses a significant public health challenge facing an aging population. The proposed study is innovative, characterized by (1) focusing on sex-specific study in older women; (2) addressing time-varying risk factors that may have significant predictive effects on the study outcomes. (3) We will test whether there are potential modification effects of APOE on the association between the study of exposures and outcomes. The scientifically promising aspects of the study are the fact that it is able to test the natural development of MCI and dementia using data from an unique large-scale population-based study, the Women’s Health Initiative Memory Study. Findings of the study will be disseminated through scientific meetings and research articles published in high impact journals, and add new insights into the prevention and control of MCI and dementia.