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

绝经后和老年妇女是阿尔茨海默病（AD）研究中的弱势群体 和相关痴呆症（ADRD）。ADRD影响女性多于男性，越来越多的证据表明， 不同性别的风险因素。虽然继续寻求有效的预防，但我们只有有限的 了解环境风险因素，特别是那些在晚年可以改变的因素。在美国，有很好的- 记录了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。虽然这是确定可修改的 环境因素，调查ADRD风险的国家内地理差异仍然是一个很大的挑战。 挑战，因为它需要大量的投资，以遵循一个前瞻性的队列，并雇用相同的，良好的- 经验证的协议，以确定事件痴呆症在多个地点的人口。在一个全国性的老年人队列中， 在妇女健康倡议记忆研究（WHIMS）中，我们最近报道了第一个证据， AD发病率的地理差异。我们的初步数据还表明， 污染物是一种与ADRD风险增加相关的新型神经毒素，但ADRD的地理差异不是 心血管疾病和其他传统的风险因素解释。这些发现强调了关键的 需要审查其他环境-社会决定因素，并进一步阐明机械调解人。到 为了经济高效地解决这些知识差距，我们建议研究特征鲜明且地理位置优越的- WHIMS（n=7479，年龄65-80岁）和年轻女性WHIMS中绝经后和老年女性的不同队列 女性（WHIMS-Y; n=1336，年龄50-54），自1996年以来每年随访一次。我们将利用现有的数据 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 脂肪酸）和更新结果（痴呆亚型;年度神经心理学评估;纵向 脑结构MRI）到2016年。在目标1中，我们将定义预测以下疾病的认知内表型（CEP）： ADRD，并研究居住地理指标如何影响CEP及其进展。在目标2中，我们将 构建多变量结构方程模型（SEM），并检验假设的环境 这些因素导致CEP和ADRD风险的地理差异。在目标3中，我们将使用SEM评估大脑 结构相关物（前额叶皮质;海马-杏仁复合体;白色物质）和小血管 局部缺血、肺水肿介导CEP中的地理环境差异。在目标4中，我们将探讨 环境相互作用在塑造CEP和ADRD风险的地理差异。一个多学科小组已经 聚集在一起，共同致力于这一新兴的环境-社会神经科学领域的健康 人口大脑老化的差异。从R 01中获得的预期新知识将有助于识别 不利的暴露和保护过程易于干预，以发展循证的， 机械知情的预防策略，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.