Alzheimer's Disease & Related Dementias: Geography, Environments, and Mechanisms

在阿尔茨海默病(AD)的研究中，绝经后和老年妇女是一个弱势群体 和相关痴呆症(ADRD)。ADRD影响的女性比男性更多，越来越多的证据表明 不同性别的危险因素不同。虽然对有效预防的探索仍在继续，但我们只有有限的 关于环境风险因素的知识，特别是那些在晚年可以改变的因素。在美国，有很多- 记录在案的痴呆症患病率和死亡率的地区差异，但没有研究提供 对可改变的环境因素的有用见解。虽然这是识别可修改的 环境因素，调查国家内部ADRD风险的地理差异仍然是一个很大的问题 挑战，因为它需要大量投资来跟随预期的队列并雇用相同的、良好的- 确定多地点人群中偶发痴呆症的有效方案。在全国范围内的老年人队列中 女性健康倡议记忆研究(Whims)，我们最近报告了第一个证据 阿尔茨海默病发病率的地理差异。我们的初步数据还表明，暴露在区域空气中 污染物是一种新的神经毒素，与ADRD风险增加有关，但ADRD的地理差异不是 由心血管疾病和其他常规风险因素解释。这些发现突显了 需要审查其他环境-社会决定因素，并进一步阐明机械的调解因素。至 为了经济高效地解决这些知识差距，我们建议研究具有良好特性和地理位置的- 各种不同的绝经后和老年女性心血来潮(n=7479，年龄65-80岁)和年轻女性的心血来潮 女性(Whims-Y；n=1336，年龄50-54岁)，自1996年以来每年都进行跟踪调查。我们将利用现有的数据 关于假设的环境决定因素(环境空气污染物；心理社会因素；饮食模式和 )和更新结果(痴呆亚型；年度神经心理评估；纵向 结构性脑核磁共振)至2016年。在目标1中，我们将定义认知内表型(CEP)预测 ADRD，并考察居住地理指标如何影响CEP及其进展。在目标2中，我们将 构建多元结构方程模型(SEM)并检验假设的环境是否 造成CEP和ADRD风险的地域差异的因素有很多。在目标3中，我们将使用SEM来评估大脑 结构相关(前额叶皮质；海马-杏仁复合体；白质)和小血管 缺血，推测介导了CEP的地理环境差异。在目标4中，我们将探索 环境相互作用在形成CEP和ADRD风险的地理差异中的作用。一个多学科团队已经 聚集在一起，共同致力于环境-社会神经科学这一新兴领域的健康 人口脑老化的差异。预计从R01中获得的新知识将有助于确定这两个 可干预的不良暴露和保护过程，以发展以证据为基础的、 机制知情的预防战略，以减少ADRD风险的地理差异。

Post-menopausal and older women are a vulnerable population in the research on Alzheimer’s disease (AD) and related dementias (ADRD). ADRD affects more women than men, and increasing evidence indicates different risk factors by sex. While the search for effective prevention continues, we only have limited knowledge about environmental risk factors, especially those modifiable in late life. In the US, there are well- documented regional differences in both prevalence and mortality of dementia, but no studies have provided useful insights for modifiable environmental factors. Although an important step towards identifying modifiable environmental factors, investigating within-country geographic differences in ADRD risks remains a great challenge, as it requires substantial investment to follow a prospective cohort and employ identical, well- validated protocols to ascertain incident dementia in multi-site populations. In a nationwide cohort of older women from the Women’s Health Initiative Memory Study (WHIMS), we recently reported the first evidence of geographic disparities in AD incidence. Our preliminary data also indicate that exposure to regional air pollutants is a novel neurotoxin associated with increased ADRD risks, but the ADRD geo-disparities were not explained by cardiovascular disease and other conventional risk factors. These findings highlight the critical need to examine other environmental-social determinants and further elucidate the mechanistic mediators. To address these knowledge gaps cost-efficiently, we propose to study the well-characterized and geographically- diverse cohorts of postmenopausal and older women in WHIMS (n=7479, aged 65-80) and WHIMS of Younger Women (WHIMS-Y; n=1336, aged 50-54), both followed annually since 1996. We will capitalize on extant data on hypothesized environmental determinants (ambient air pollutants; psychosocial factors; dietary patterns and fatty acids) and update outcomes (dementia subtype; annual neuropsychological assessment; longitudinal structural brain MRI) through 2016. In Aim 1, we will define the cognitive endophenotypes (CEP) predictive of ADRD, and examine how indicators of residential geography affect CEP and its progression. In Aim 2, we will construct multivariate structural equation models (SEMs) and test whether the hypothesized environmental factors contribute to the geo-disparities in CEP and ADRD risks. In Aim 3, we will use SEMs to evaluate brain structural correlates (prefrontal cortex; hippocampal-amygdalar complex; white matter) and small-vessel ischemia, putatively mediating the geo-environmental disparities in CEP. In Aim 4, we will explore the environmental interactions in shaping the geo-disparities in CEP and ADRD risks. A multidisciplinary team has been assembled to work together on this emerging field of environmental-social neurosciences on health disparities in population brain aging. Expected new knowledge gained from this R01 will help identify both adverse exposures and protective processes amenable to intervention, towards developing evidence-based, mechanistically-informed prevention strategies to reduce the geographical disparities in ADRD risks.