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

项目摘要/摘要 美国黑人经历了不成比例的心血管疾病(CVD)危险因素负担 阿尔茨海默病和相关痴呆(ADRD)。研究确定了中年(~45岁至65岁) 血脂异常是ADRD的危险因素。与白人相比，美国黑人的血脂特征更有利 或拉丁裔，但他们中年血脂异常的发生率更高。这种看似自相矛盾的关系 在中年血脂谱良好但中年血脂异常高发和ADRD高危人群之间 美国黑人的研究一直严重不足。血脂在神经退行性疾病中起着至关重要的作用， 流行病学和代谢学研究已经确定了常用的检测血脂(总胆固醇，高密度脂蛋白 胆固醇、低密度脂蛋白胆固醇和甘油三酯)以及神经鞘脂(神经酰胺)作为认知能力的预测指标 衰老。以前的工作在很大程度上忽略了血脂对美国黑人和少数人ADRD风险的贡献 在这一高危人群中，研究人员研究了神经酰胺与认知老化和ADRD的关系。 该项目将利用来自NIH/NIA资助的两项队列研究Kaiser的超过40年的纵向数据 健康老龄化和多样化生活体验(KANDLE)研究和非洲健康老龄化研究 美国人(STAR)，更好地了解血脂在黑人认知老化和ADRD中的作用 美国人。这项研究计划的科学目标是描述青春期早期(~ 30岁)总胆固醇、高密度脂蛋白、低密度脂蛋白、甘油三酯以及新型脂质 生物标记物，神经酰胺，晚年认知功能减退，ADRD，和神经退行性变的MRI标志物 全黑人老年人队列中的血管脑损伤。这项拟议的研究试图：1)定义 成人早期血脂与认知老化和ADRD；2)检查遗传(APOE)和心理社会(种族主义) 作为潜在影响修饰物的因素；以及3)决定成年早期血脂水平的关系 老年认知功能减退和ADRD部分由中年(~45-65岁)心脏代谢调节 疾病(高血压、糖尿病、肥胖和血脂异常)。针对患病率较高的老年美国黑人 在心血管疾病危险因素和痴呆症风险不成比例的情况下，预防ADRD具有巨大的健康和 经济后果。这项研究将得到详细的培训计划的支持，该计划基于 加州大学戴维斯分校，在全国和 国际公认的ADRD、血脂、痴呆症和认知老化研究人员。培训的基础将是 申请人在心血管疾病和痴呆症流行病学方面的背景，包括 生命过程理论和现代因果推理方法，血脂生物学，心理测量测试，以及 神经影像生物标志物的测量和建模。综合研究和培训将为 申请者成功过渡到血管贡献差异的独立研究人员 阿德勒。

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.