Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study

项目总结/摘要 在阿尔茨海默病（AD）研究中，为了减轻疾病负担，迫切需要更好地利用 前瞻性队列。对于以人口为基础的群组， 种族/少数民族。有鉴于此，我们在2010年开始了AD和相关痴呆（ADRD）研究。 多种族队列研究（MEC; 1993年至今），美国最大和最多样化的癌症队列， 基线时由五个血统（非洲人、日本人、拉丁美洲人、夏威夷土著人、白色人）的> 215，000名成年人组成 在夏威夷和南加州采样。我们观察到AD发生率和已知的危险因素 MEC-医疗保险关联数据中的关联与基于临床的研究中报告的关联高度可比， 这保证了用于AD/ADRD研究的MEC数据的质量和通用性。我们还发现 夏威夷土著人和非裔美国人中AD风险和APOE e4频率显著较高， 与白人相比。这一发现和其他重要发现说明了MEC对AD/ADRD的独特价值 差距研究。然而，一个经常出现的问题是，MEC中的AD/ADRD定义仅基于 医疗保险索赔，因此，可能包括错误分类。基于医疗保险索赔的疾病结果是 与临床诊断相对照。然而，这种方法对于AD/ADRD不太可靠，因为电流 诊断金标准，神经成像或脑脊液生物标志物，通常是难以接近或无法忍受的， 特别是对种族/少数民族、农村居民和老年人，而临床评估 没有这些生物标志物的情况下，已知准确性低。在这种情况下，血液为基础的制造商（BBM）新 经FDA批准用于AD的初步筛选，磷酸化tau-181（pTau-181）提供了一个重要的机会， 在MEC中有力地验证AD病例，同时通过以下方式及时评估BBM 种族/民族。因此，我们建议（目的1）复制血浆pTau-181和~570之间的关联 使用嵌套病例中首次医疗保险索赔后5年内采集的存档血液的AD事件病例- 对照研究我们将根据性别、人种/种族和APOE e4对总体相关性进行评估。我们也将（Aim） 2)确定AD病例中血浆pTau-181的决定因素，在病例相关，人口统计学（性别， 种族/民族、年龄队列、教育、社区社会经济地位）、遗传（APOE、多基因风险评分） 和可改变的风险因素（血管代谢疾病史、体力活动、饮食质量、睡眠时间） 从长期、前瞻性随访中获得的特征，以了解生物标志物的变化。 拟议的工作属于现行MEC资助范围（U 01 CA 164973; 2022-2027），因为它将增强 研究遗传、生活方式和环境风险因素的队列基础设施， 美国多个种族/族裔群体中的成年人慢性疾病。考虑到癌症的深度和广度， MEC支持的其他慢性病研究，这项基于BBM的验证建议， 对AD的研究可能会刺激一系列额外的活动，从而导致AD/ADRD研究的进展。

PROJECT SUMMARY / ABSTRACT In Alzheimer's disease (AD) research to mitigate the disease burden, there is a critical need to better utilize prospective cohorts. The need is especially great for population-based cohorts that include significant numbers of racial/ethnic minority individuals. In light of this, we initiated AD and related dementias (ADRD) research in the Multiethnic Cohort Study (MEC; 1993-current), the largest and most diverse cancer cohort in the US, composed at baseline of >215,000 adults of five ancestries (African, Japanese, Latino, Native Hawaiian, White) sampled in Hawaii and Southern California. We observed that the AD rates and the known risk factor associations in the MEC-Medicare linkage data are highly comparable to those reported in clinic-based studies, which assures the quality and generalizability of the MEC data for AD/ADRD research. We also found substantially higher AD risks and APOE e4 frequencies among Native Hawaiians as well as African Americans, compared to Whites. This and other important findings speak to the unique values of the MEC for AD/ADRD disparities research. However, one recurrent concern is that the AD/ADRD definitions in MEC are solely based on Medicare claims and, thus, may include misclassifications. Medicare claims-based disease outcomes are validated against clinical diagnosis. This approach is, however, less reliable for AD/ADRD because the current diagnostic gold standard, neuroimaging or cerebrospinal fluid biomarkers, is often inaccessible or intolerable, particularly to individuals of racial/ethnic minorities, rural residences and older ages, while clinical assessment without these biomarkers has known low accuracy. In this context, the blood-based maker (BBM) newly approved by FDA for initial screening of AD, phosphorylated tau-181 (pTau-181), provides a vital opportunity to robustly validate AD cases in MEC, while at the same time producing timely evaluation of the BBM by race/ethnicity. Thus, we propose to (Aim 1) replicate the association between plasma pTau-181 and ~570 incident AD cases using archived blood collected within 5 years of the first Medicare claim in a nested case- control study. We will evaluate the association overall and by sex, race/ethnicity and APOE e4. We will also (Aim 2) identify the determinants of plasma pTau-181 in AD cases, among the case-related, demographic (sex, race/ethnicity, age cohort, education, neighborhood socioeconomic status), genetic (APOE, polygenic risk score) and modifiable risk factor (vascular-metabolic disease history, physical activity, diet quality, sleep duration) characteristics available from the long-term, prospective follow-up, in order to understand the biomarker variation. The proposed work is within the scope of the active MEC grant (U01 CA164973; 2022-2027), as it will enhance the cohort infrastructure for investigations of genetic, lifestyle and environmental risk factors for an important chronic disease in US adults across multiple racial/ethnic groups. Given the breadth and depth of the cancer and other chronic disease research that has been supported by the MEC, this proposed BBM-based validation and investigation of AD is likely to stimulate an array of additional activities leading to progress on AD/ADRD research.