Understanding Biological and Lifestyle Contributions to Alzheimer's Disease Pathology and Clinical Profiles in Black Women: Defining Prevention Targets in High Risk Groups

项目总结/摘要 女性阿尔茨海默病（AD）的发病率更高，并且往往表现出比男性更积极的AD特征。 男性，具有更大的病理性tau负担和更陡峭的认知下降。AD的患病率也因 黑人老年人的发病率高于白色老年人。然而，人们对黑色广告知之甚少 在研究中被排除在历史之外的个人。关于种族和性别的交叉点， 在AD中。在这项提案中，我们的目标是研究性别和/或种族差异的生物学（炎症，胰岛素抵抗）， [IR])途径和身体活动可能会导致tau蛋白积累和认知能力下降， 在老年黑人女性中有患AD的风险。我们专注于潜在的可改变的风险/保护因素， 最近有大量证据表明，改变这些因素可以非常有效地延缓甚至预防 认知能力下降我们自己的初步研究表明，女性可能比男性更容易受到 炎症对磷酸化tau（p-tau）水平和认知功能的不利影响。还有 有证据表明，某些生活方式因素，包括体力活动，对AD相关的结果有更大的影响 例如女性与男性之间的tau蛋白。鉴于身体活动和炎症之间的联系，我们建议 研究炎症和身体活动在其对tau蛋白和认知功能的贡献中的相互作用。 老年黑人女性患AD的风险下降。由于IR是炎症的关键驱动因素， 糖尿病前期/糖尿病在黑人成年人中更高，我们将研究IR如何影响tau蛋白的积累和认知功能。 下降至关重要的是，要在健康的社会决定因素的背景下审查这些关系， 健康结果的驱动因素，如炎症和IR，特别是在黑人妇女中。因此我们 提出一项前瞻性研究，评估所有感兴趣的变量及其相互作用途径。拟议 这项研究将建立在一项正在进行的试点研究的基础上，该研究将在研究结束时收集30名白色妇女的这些变量 (June，2022年），但将代表一个更有针对性和侵入性较小的研究，以加强招募 未被充分研究但风险较高的老年黑人妇女群体。我们建议在两个地点招募黑人妇女， 利用现有的研究登记册的黑人妇女在洛杉矶，和其他利用当地 社区联系和以前的研究经验，在圣地亚哥创建一个新的队列。我们将使用一个 以社区为基础的参与性研究方法，涉及各级决策的招聘 涉及社区咨询委员会。我们将测量血液中的炎症标志物、IR、体力活动和 地区痴呆指数是我们对100名有AD风险的黑人妇女感兴趣的主要社会决定因素， 将这些测量与认知功能的变化和血浆中测量的tau的积累相关联， 两年期。该项目将有助于缩小我们对AD风险因素的理解方面的关键差距 妇女通过检查生物标志物和健康的社会决定因素，在这个研究不足，但高度- 弱势群体。此外，我们的研究结果将为影响这些机制的风险降低策略提供信息。

PROJECT SUMMARY/ABSTRACT Women have higher rate of Alzheimer's disease (AD) and tend to show a more aggressive profile of AD than men, with greater pathological tau burden and steeper cognitive decline. The prevalence of AD also differs by race with higher rates among Black versus White older adults. Yet, very little is known about AD in Black individuals given their historical exclusion in research. Even less is known about the intersection of race and sex in AD. In this proposal, we aim to study how sex- and/or race-disparate biological (inflammation, insulin resistance [IR]) pathways and physical activity potentially contribute to tau accumulation and cognitive decline specifically among older Black women at-risk for AD. We focus on potentially modifiable risk/protective factors given the recent surge in evidence that modification of these factors can be highly effective in delaying or even preventing cognitive decline. Our own preliminary work indicated that women may be more susceptible than men to the adverse effect of inflammation on levels of phosphorylated tau (p-tau) and cognitive function. There is also evidence that certain lifestyle factors, including physical activity, have a greater impact on AD-related outcomes such as tau in women versus men. Given links between physical activity and inflammation, we propose to investigate the interplay between inflammation and physical activity in their contributions to tau and cognitive decline in older Black women at risk for AD. Since IR is a key driver of inflammation, and the rates of prediabetes/diabetes are higher in Black adults, we will examine how IR impacts tau accumulation and cognitive decline. It is critical to examine these relationships in the context of social determinants of health, which are a driving factor in health outcomes such as inflammation and IR particularly in Black women. To achieve this, we propose a prospective study that will assess all variables of interest and their interactive pathways. The proposed study will build upon an ongoing pilot study that will collect these variables in 30 White women by study end (June, 2022), but will represent a more targeted and less invasive study in order to enhance recruitment in the understudied yet higher risk group of older Black women. We propose to recruit Black women at two sites, one leveraging an existing research registry of Black women in Los Angeles, and the other leveraging local community connections and previous research experience to create a new cohort in San Diego. We will use a community-based participatory research approach to recruitment that involves decision making at each level involving a Community Advisory Board. We will measure inflammatory markers in blood, IR, physical activity and the Area Deprivation Index as our primary social determinant of interest in 100 Black women at-risk for AD and relate these measures to changes in cognitive function and accumulation of tau, measured in plasma, over a two-year period. This project will help to close critical gaps in our understanding of risk factors for AD in Black women by examining biomarkers and social determinants of health in this under-researched yet highly- vulnerable group. Furthermore, our findings will inform risk reduction strategies that influence these mechanisms.