Using Genetic and Blood Metabolites to Understand the Risk of Alzheimer's Disease in Latinos

利用遗传和血液代谢物了解拉丁裔患阿尔茨海默病的风险

• 批准号: 10845817
• 负责人: Tamar Sofer
• 金额: $ 3.66万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10845817
• 关键词: Using; Genetic; Blood; Metabolites; Understand

U.S. Latinos are highly diverse, with individuals originating from central and south America, as well as the Caribbean. Latinos are socioeconomically disadvantaged compared to U.S. Whites, and suffer from a higher prevalence of Alzheimer’s disease and related dementia. Genetic determinants of Alzheimer’s disease may be somewhat different in Latinos compared to Whites: in preliminary results, we found that genetic background, in the form of proportion of genome inherited from Amerindian (Native American) ancestors mitigates the detrimental effect of the APOE-𝜖𝜖4 variants on cognitive decline in individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). This suggests heterogeneity in genetically-based mechanisms underlying neurocognitive decline in Latinos. Untargeted metabolomics is a promising approach to develop potential biomarkers for human disease. Previous metabolomics studies identified potential biomarkers for Alzheimer’s disease and for cognitive traits in a cross- sectional manner, however, very little work was done specifically in Latinos, and the genetics and metabolomics have not been integrated for risk prediction, apart from using APOE-𝜖𝜖4. Here, we propose to utilize a dataset including ~1,500 older Latino adults from the HCHS/SOL with untargeted metabolomics measured at a baseline visit, and neurocognitive function estimated in both the baseline and a follow-up visit. Our goals are: (1) develop preliminary biomarkers for aging-related cognitive decline phenotypes (e.g. change in global cognitive function, mild cognitive impairment); (2) study the genetic basis of the association of metabolites with cognitive decline, and study potential heterogeneity by genetic background; and (3) form recommendations and a grant application to support a larger research program utilizing genetics and metabolomics, and potentially other ‘omics, to develop biomarkers of Alzheimer’s disease in diverse populations, and study underlying mechanisms.

美国拉丁美洲人是高度多样化的，与个人来自中美洲和南美洲，以及 加勒比海与美国白人相比，拉丁美洲人在社会经济上处于不利地位， 阿尔茨海默病和相关痴呆症的患病率。阿尔茨海默病的遗传决定因素可能是 与白人相比，拉丁美洲人有些不同：在初步结果中，我们发现遗传背景， 从美洲印第安人（美洲原住民）祖先继承的基因组比例的形式减轻了 APOE-β4变异体对西班牙裔人群认知能力下降的不利影响 健康研究/拉丁美洲人研究（HCHS/SOL）。这表明基于遗传机制的异质性 潜在的神经认知能力下降 非靶向代谢组学是开发人类疾病潜在生物标志物的一种有前途的方法。先前 代谢组学研究确定了阿尔茨海默病和认知特征的潜在生物标志物， 然而，以分段的方式，很少有专门针对拉丁美洲人的工作，遗传学和代谢组学 除了使用APOE-β4外，还没有被整合用于风险预测。在这里，我们建议利用数据集 包括来自HCHS/SOL的约1，500名老年拉丁裔成年人，基线时测量了非靶向代谢组学 在基线和随访访视中评估神经认知功能。我们的目标是：（1）发展 用于衰老相关的认知衰退表型的初步生物标志物（例如整体认知功能的变化， 轻度认知损害）;（2）研究代谢物与认知下降相关的遗传基础， 并研究遗传背景的潜在异质性;（3）形成推荐和资助 应用程序，以支持更大的研究计划，利用遗传学和代谢组学，并可能其他 “组学”，在不同人群中开发阿尔茨海默病的生物标志物，并研究潜在的机制。