Epidemiologic, imaging and pathological studies of the role of blood pressure variability in dementia etiology

申请编号：1 K99 AG 071742 -01 PI：MA，YUAN 修改项目摘要/摘要部分 血压变异性在阿尔茨海默病和相关痴呆病因学中作用的流行病学、影像学和病理学研究 项目摘要 老年人中阿尔茨海默病和相关痴呆（ADRD;在下文中，与痴呆互换使用）的病因学是多因素的，并且血管风险因素，尤其是高血压，是主要的可改变的贡献者。然而，血压（BP）和痴呆症之间的关系还远不清楚。不同时期血压变异性的增加与心血管疾病和死亡风险有关，与静态血压水平无关。新出现的证据也表明，血压变异性是阿尔茨海默病和相关痴呆症的一个新的危险因素。但是，由于缺乏评估BP变异性的标准和缺乏对潜在机制的了解，BP变异性在阿尔茨海默病和相关痴呆的风险分层和预防方面的临床转化受到阻碍。该项目的目标是：1）全面量化BP变异性与阿尔茨海默病和相关痴呆症之间的流行病学关系; 2）确定BP变异性与阿尔茨海默病和相关痴呆症之间的因果关系。为了实现这些目标，将分析来自美国和欧洲的6项前瞻性队列研究的数据：心脏病研究、鹿特丹研究、三城市研究、社区动脉粥样硬化风险研究和拉什宗教秩序研究以及记忆和衰老项目。在目标1中，将使用一致的方法，通过汇总来自上述6项队列研究的个体数据（n~ 31，274），量化3种类型的BP变异性（访视间变异性、心跳间变异性和姿势变异性）与阿尔茨海默病和相关痴呆风险之间的关系。目的2和3将进一步研究这些流行病学关系的机制。具体而言，在目标2中，将使用因果中介分析来确定脑小血管疾病在多大程度上介导了具有脑MRI数据的参与者中BP变异性与阿尔茨海默病和相关痴呆症风险之间的关系。目的3（R 00阶段）使用神经病理学和神经影像学数据将研究扩展到阿尔茨海默病（AD）病理学，其中BP变异性，血管病理学，AD病理学和阿尔茨海默病及相关痴呆症风险之间的相互作用将被表征。该K99项目将加强PI之前在医学和流行病学方面的培训，并进一步扩展她在以下方面的专业知识：1）因果推理方法，2）采用神经影像学和神经病理学数据，3）将临床和机制相关性纳入流行病学研究。该项目将使PI成为一名独立的研究人员，使用先进的流行病学方法和跨学科技能，为预防阿尔茨海默病和相关痴呆症做出重大贡献。

Application Number: 1 K99 AG071742-01 PI: MA, YUAN Modified Project Summary/Abstract Section Epidemiologic, imaging and pathological studies of the role of blood pressure variability in the etiology of Alzheimer's disease and related dementias Project Summary The etiology of Alzheimer's disease and related dementias (ADRD; hereinafter, used interchangeably with dementia) in older adults is multifactorial, and vascular risk factors, especially hypertension, are major modifiable contributors. However, the relationship between blood pressure (BP) and dementia is far from clear. Increased BP variability over different periods has been linked to cardiovascular disease and mortality risk independent of static BP levels. Emerging evidence has also suggested BP variability as a novel risk factor for Alzheimer's disease and related dementias. But the clinical translation of BP variability for the risk stratification and prevention of Alzheimer's disease and related dementias has been hampered by the lack of standards for assessing BP variability and the lack of knowledge on the underlying mechanisms. The goals of this project are to 1) comprehensively quantify the epidemiological relationship between BP variability and Alzheimer's disease and related dementias and 2) identify the causal pathways linking BP variability to Alzheimer's disease and related dementias. To accomplish these, the data from 6 prospective cohort studies across the US and Europe will be analyzed: the Framingham Heart Study, the Rotterdam Study, the Three-City Study, the Atherosclerosis Risk in Communities Study, and the Rush Religious Orders Study and Memory and Aging Project. In Aim 1, the relationship between 3 types of BP variability (visit-to-visit variability, beat-to-beat variability, and postural variability) and the risk of Alzheimer's disease and related dementias will be quantified by pooling individual data (n~31,274) from the above 6 cohort studies using consistent approaches. Aims 2 and 3 will further investigate the mechanisms underlying these epidemiologic relationships. Specifically, in Aim 2, the extent to which cerebral small vessel disease mediates the relationship between BP variability and the risk of Alzheimer's disease and related dementias among participants with brain MRI data will be determined using causal mediation analysis. Aim 3 (R00 phase) extends the investigation to Alzheimer’s disease (AD) pathology using neuropathology and neuroimaging data, where the interplay between BP variability, vascular pathology, AD pathology and the risk of Alzheimer's disease and related dementias will be characterized. This K99 project will enhance the PI’s prior training in medicine and epidemiology and further expand her expertise in 1) causal inference methods, 2) employing neuroimaging and neuropathology data, and 3) incorporating clinical and mechanistic relevance in epidemiological studies. This project will enable the PI to establish herself as an independent researcher using advanced epidemiological methods and interdisciplinary skills to make significant contributions to the prevention of Alzheimer's disease and related dementias.