Air pollution and early signs of dementia

接触空气污染是许多慢性病的关键健康风险因素，并与痴呆症有关。 然而，在我们对空气污染如何导致痴呆症的认识上存在一些空白，这些 是我们提案的重点。首先，大多数空气污染暴露研究没有区分 痴呆症。其次，他们倾向于依赖横截面分析。第三，他们不认为痴呆症 生物标志物。为了解决这些问题，我们选择专注于衰老和大脑健康的纵向研究 我们可以区分导致痴呆症的两种最常见的原因，即阿尔茨海默病(AD) 以及血管认知障碍(VCI)，这两种疾病也可能共存。具体地说，我们将利用来自四个方面的数据 对大脑老化的不同纵向研究，包括来自亚特兰大大都会和 佐治亚州的年龄、社会经济地位和认知地位各不相同。这些纵向研究 重点关注未受影响或受影响最小的人，因为研究这些人能为我们提供最好的 确定AD和VCI对整体认知的相对贡献的机会。每项研究都会执行 详细的神经认知测试、AD的标准脑脊液生物标志物和脑体积 AD和VCI的生物标志物，我们将分配高分辨率细颗粒物环境空气污染浓度 (PM2.5及其组成部分)给所有研究参与者，根据他们现在和过去的住址。 利用这些丰富的数据，可以测试空气污染与AD不同方面之间的关联-或者 VCI。为了了解空气污染如何导致AD、VCI或两者兼而有之，我们将调查它们之间的关联 空气污染与以主观记忆主诉、短时记忆为特征的阿尔茨海默病指标 或基于神经认知测试的语言障碍，阳性的AD-CSF生物标记物(即Aβ42，TOTAL-TAU， 和磷酸化Tau)和较小的海马体体积；2)调查空气污染和 以执行功能受损为特征的VCI指标(通过神经认知测试来衡量) 和脑MRI测量的脑微血管缺血改变；以及3)研究两者之间的关系 空气污染与加速的表观遗传衰老和痴呆相关的dNaM模式之间的关系。至关重要的是，我们将 还要评估性别、种族/民族、社会经济因素、遗传风险、抑郁症、心血管疾病 糖尿病改变了空气污染与AD和VCI指标之间的联系。这项研究将 提供有关空气污染如何影响两种最常见致病原因的早期表现的生物学见解 痴呆症(AD和VCI)以及修饰因素(例如，性别和种族/族裔)如何影响脆弱性。因此，我们 预计这项工作将对实地产生重要和持久的影响。

Air pollution exposure is a critical health risk factor for many chronic illnesses and has been linked to dementia. However, there are a number of gaps in our knowledge of how air pollution contributes to dementia, and these are the focus of our proposal. First, most air pollution exposure studies do not differentiate between causes of dementia. Second, they tend to rely on cross-sectional analyses. Third, they do not consider dementia biomarkers. To address those issues, we chose to focus on longitudinal studies of aging and brain health where we can distinguish among two of the most common causes of dementia, i.e., Alzheimer's disease (AD) and vascular cognitive impairment (VCI), which may also co-exist. Specifically, we will leverage data from four diverse longitudinal studies of brain aging including more than 23,000 participants from metro-Atlanta and Georgia spanning a wide range of age, socioeconomic status, and cognitive status. These longitudinal studies focus on unaffected or minimally affected individuals since studying those individuals affords us the best chance of determining the relative contribution of AD and VCI to overall cognition. Each study performs detailed neurocognitive testing, standard cerebrospinal fluid (CSF) biomarkers of AD and brain volumetric biomarkers of AD and VCI and we will assign high-resolution fine particle ambient air pollution concentrations (PM2.5 and its components) to all study participants based on their current and past residential addresses. Leveraging these rich data allows to test for association between air pollution and different facets of AD- or VCI. To understand how air pollution contributes to AD, VCI, or both, we will 1) investigate associations between air pollution and indicators of AD characterized by subjective memory complaints, short-term memory or language impairment based on neurocognitive testing, positive AD CSF biomarkers (i.e., Aβ42, total-Tau, and phospho-Tau) and smaller hippocampal volumes; 2) investigate associations between air pollution and indicators of VCI characterized by impairment in the executive function (measured by neurocognitive testing) and cerebral microvascular ischemia changes measured by brain MRI; and 3) investigate associations between air pollution and accelerated epigenetic aging and dementia-related DNAm patterns. Critically, we will also evaluate how sex, race/ethnicity, socioeconomic factors, genetic risk, depression, cardiovascular disease and diabetes modify the associations between air pollution and indicators of AD and VCI. This study will provide biological insights of how air pollution affects early manifestations of the two most common causes of dementia (AD and VCI) and how modifiers (e.g., sex and race/ethnicity) affect vulnerability. Therefore, we expect this work to have an important and sustained impact on the field.