Traffic-Related Air Pollutants and Alzheimer's Disease: Risk, Susceptibility and Mechanisms in Women

项目-1旨在调查交通相关空气污染（TRAP）对风险的贡献， 阿尔茨海默病（AD）和相关痴呆（ADRD）的易感性和机制 来自妇女健康倡议（WHI）记忆研究（WHIMS）的妇女队列。ADRD影响更多 越来越多的证据表明，不同性别的风险因素不同，这表明需要 分别为妇女和男子确定可改变的环境因素。在过去的二十年里， 数据表明，暴露于包括TRAP在内的室外空气污染物是一种新的环境决定因素 大脑老化的迹象尽管有强有力的证据表明TRAP诱导的神经毒性（例如，显示Aβ存款增加 在项目-3）中，关于TRAP暴露是否以及如何影响脑老化的人类数据仍然有限， 前后矛盾以往的研究有明显的局限性：（1）缺乏ADRD增加的前瞻性证据 与TRAP相关的风险;（2）不是基于我们目前对早期认知变化，生物标志物， AD的神经生物学分类;（3）未研究老年前TRAP效应导致的AD风险 (e.g.,年龄< 55岁）;和（4）提供有限的了解大脑结构和神经病理学连接TRAP， 早期认知缺陷或AD风险增加。为了以具有成本效益的方式弥补这些知识差距，项目1 建立在两个特点鲜明和地理多样化的中年和老年妇女群体， 年轻女性的WHIMS（WHIMS-Y; n=1346，初始年龄50-54）和WHIMS-MRI（n=1403，初始 年龄65-80岁），自1996年以来每年随访一次，两者都有可比的情景记忆纵向评估 和执行功能。我们进一步利用NIEHS资助的WHIMS中的R 01， 由MESA-Air（“动脉粥样硬化和空气污染的多种族研究”）团队开发的污染模型， 估计TRAP（NO2; PM2.5;暴露源/成分）。在Core B1的支持下，我们将小说 群体神经影像学方法来研究社区中的病理性脑老化， AD的临床和神经病理学分类定义在非常充分表征的样本中， 阿尔茨海默病神经影像学倡议与β-淀粉样蛋白和神经元损伤的生物标志物。国家 艺术调解和神经计算分析将进行检查TRAP影响的大脑 结构和神经病理学途径的早期认知缺陷或MRI生物标志物， AD风险增加。目标1将确定TRAP对预测风险增加的早期生物标志物的影响 AD、轻度认知障碍和老年女性的临床前AD。目标2将检查以下各项的关联 认知能力下降，反映了在晚年之前/期间暴露于TRAP的早期AD。在目标3中，我们将同时 有针对性的和不可知的方法与高维神经计算，以阐明大脑结构， 神经病理学介导TRAP对病理性脑老化的影响。目标4将评估APOE 4是否 和血管性脑损伤增加了对TRAP暴露的神经毒性作用的易感性。

Project-1 is designed to investigate the contribution of traffic-related air pollution (TRAP) to the risk, susceptibility and mechanisms of Alzheimer’s disease (AD) and related dementias (ADRD) in a nationwide cohort of women from the Women’s Health Initiative (WHI) Memory Studies (WHIMS). ADRD affects more women than men, and increasing evidence indicates different risk factors by sex, pointing to the need to identify modifiable environmental factors separately for women and men. In the last two decades, compelling data have shown that exposure to outdoor air pollutants including TRAP is a novel environmental determinant of brain aging. Despite the strong evidence for TRAP-induced neurotoxicity (e.g., increased Aβ deposit shown in Project-3), human data on whether and how TRAP exposure effects brain aging remain limited and inconsistent. Previous studies had notable limitations: (1) lacking prospective evidence for an increased ADRD risk associated with TRAP; (2) not based on our current understanding of early cognitive change, biomarkers, and neurobiological classification of AD; (3) not studying AD risk resulting from TRAP effects before late life (e.g., aged < 55); and (4) providing limited insight on the brain structure and neuropathology linking TRAP to early cognitive deficits or an increased risk of AD. To address these knowledge gaps cost-efficiently, Project-1 builds on two well-characterized and geographically-diverse cohorts of mid-aged and older women in the WHIMS of Younger Women (WHIMS-Y; n=1346, inception age 50-54) and WHIMS-MRI (n=1403, inception age 65-80) followed annually since 1996, both with comparable longitudinal assessments on episodic memory and executive function. We further capitalize an NIEHS-funded R01 in WHIMS which employs sophisticated air pollution models developed by the MESA-Air ("Multi-Ethnic Study of Atherosclerosis and Air Pollution") team to estimate TRAP (NO2; PM2.5; exposure sources/components). Supported by the Core B1, we take the novel population neuroimaging approach to studying pathological brain aging in communities, drawing on both clinical and neuropathological classification of AD defined in very well-characterized samples from the Alzheimer’s Disease Neuroimaging Initiative with biomarkers of β-amyloid and neuronal injuries. State-of-the- art mediation and neurocomputational analyses will be conducted to examine the TRAP-affected brain structures and neuropathological pathways underlying the early cognitive deficits or MRI biomarkers of increased AD risk. Aim 1 will determine the impact of TRAP on early biomarkers predictive of increased risks for AD, mild cognitive impairment, and preclinical AD in older women. Aim 2 will examine the associations of cognitive decline reflecting early AD with TRAP exposure before/during late life. In Aim 3, we will take both targeted and agnostic approached with high-dimensional neurocomputation to elucidate the brain structure and neuropathology mediating the TRAP effects on pathological brain aging. Aim 4 will evaluate whether APOE4 and vascular brain injuries increase the susceptibility to the neurotoxic effects of TRAP exposure.