The Role of Lipids in Alzheimer's Disease and Related Dementias among Black Americans: Examining Lifecouse Mechanisms

项目总结/摘要 美国黑人经历了不成比例的心血管疾病（CVD）风险因素负担， 阿尔茨海默病和相关痴呆症（ADRD）。研究表明，中年（约45 - 65岁） 血脂异常是ADRD的危险因素。与白人相比，美国黑人的血脂水平更高 或拉丁美洲人，但他们在中年血脂异常的发病率更高。这种看似矛盾的关系 中年血脂状况良好，但中年血脂异常发生率高，ADRD风险高， 美国黑人一直被严重低估。脂质在神经退行性疾病中起着至关重要的作用， 流行病学和代谢组学研究已经确定了通常测试的脂质（总胆固醇，HDL 胆固醇、低密度脂蛋白胆固醇和甘油三酯）以及鞘脂（神经酰胺）作为认知功能的预测因子。 衰老以前的研究在很大程度上忽略了脂质对美国黑人ADRD风险的贡献， 研究已经检查了神经酰胺与认知老化和ADRD在这一高危人群中的关系。 该项目将利用来自两项NIH/NIA资助的队列研究的40多年的纵向数据，Kaiser 健康老龄化和多样化生活经验（KHANDLE）研究和非洲健康老龄化研究 美国人（星星），以更好地了解脂质在认知老化和ADRD中的作用， 美国人这项研究计划的科学目标是描述成年早期（~） 年龄30）总胆固醇、HDL胆固醇、LDL胆固醇和甘油三酯以及新的脂质 生物标志物、神经酰胺、晚期认知功能减退、ADRD和神经变性的MRI标志物， 全黑人老年人队列中的血管性脑损伤。拟议的研究旨在：（1）确定 认知老化和ADRD中的成年早期脂质; 2）检查遗传（APOE）和心理社会（种族主义） 因素作为潜在的影响修饰符;和3）确定是否成年早期脂质水平的关系 老年认知功能下降和ADRD部分由中年（约45 - 65岁）心脏代谢介导。 疾病（高血压、糖尿病、肥胖和血脂异常）。对于患病率高的老年黑人 心血管疾病的危险因素和痴呆症的不成比例的风险，预防ADRD有巨大的健康和 经济后果。这项研究将得到一个详细的培训计划的补充， 加州大学戴维斯分校，由全国和国际一流的导师团队指导， 国际公认的ADRD、血脂、痴呆和认知老化研究人员。培训将建立在 申请人的背景，心血管疾病和痴呆症流行病学，结合专门的培训， 生命历程理论和现代因果推理方法，脂质生物学，心理测量测试， 神经成像生物标志物的测量和建模。联合研究和培训将为 申请人成功过渡到血管贡献差异的独立研究者， ADRD。

PROJECT SUMMARY/ABSTRACT Black Americans experience a disproportionate burden of cardiovascular disease (CVD) risk factors and Alzheimer's disease and related dementias (ADRD). Studies have identified midlife (~ ages 45-65) dyslipidemia as a risk factor for ADRD. Black Americans have more favorable lipid profiles compared to Whites or Latinos, but their incidence of dyslipidemia in midlife is higher. This seemingly paradoxical relationship between favorable midlife lipid profiles yet high incidence of midlife dyslipidemia and high risk of ADRD among Black Americans has been severely understudied. Lipids play a vital role in neurodegenerative disease, and epidemiologic and metabolomic studies have identified commonly tested lipids (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides) as well as sphingolipids (ceramides) as predictors of cognitive aging. Prior work has largely overlooked the contributions of lipids to ADRD risk in Black Americans and few studies have examined the relationship of ceramides with cognitive aging and ADRD in this high-risk group. This project will leverage over 40 years of longitudinal data from two NIH/NIA funded cohort studies, the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study and the Study of Health Aging in African Americans (STAR), to better understand the role of lipids in cognitive aging and ADRD among Black Americans. The scientific objective of this research plan is to characterize the relationship of early adulthood (~ age 30) total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides as well as the novel lipid biomarker, ceramides, with late life cognitive decline, ADRD, and MRI markers of neurodegeneration and vascular brain injury in an all-Black cohort of older adults. The proposed research seeks to: 1) define the role of early adulthood lipids in cognitive aging and ADRD; 2) examine genetic (APOE) and psychosocial (racism) factors as potential effect modifiers; and 3) determine whether the relationship of early adulthood lipid levels with late life cognitive decline and ADRD is partially mediated by midlife (~ ages 45-65) cardiometabolic disease (hypertension, diabetes, obesity, and dyslipidemia). For aging Black Americans with high prevalence of CVD risk factors and at disproportionate risk of dementia, prevention of ADRD has enormous health and economic consequences. This research will be complimented by a detailed training plan based at the University of California, Davis, with guidance from an exceptional mentorship team of nationally and internationally recognized ADRD, lipids, dementia, and cognitive aging researchers. The training will build upon the applicant's background in CVD and dementia epidemiology by incorporating specialized training in lifecourse theory and modern causal inference methods, biology of lipids, psychometric testing, and measurement and modeling of neuroimaging biomarkers. The combined research and training will prepare the applicant to successfully transition to an independent researcher of disparities in vascular contributions to ADRD.