The Origins of Alzheimer Disease in African Americans

非裔美国人阿尔茨海默病的起源

• 批准号: 10704751
• 负责人: Rufus Olusola Akinyemi
• 金额: $ 520.85万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704751
• 关键词: Admixture; Africa; African; African American; African American population; African ancestry; Alzheimer' s Disease; Alzheimer' s disease risk; Astrocytes; Attitude; Autopsy; Awareness; Biological Markers; Brain; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular system; Caribbean Hispanic; Case/Control Studies; Chromosome 5; Clinical; Data; Data Set; Decision Making; Dementia; Detection; Diagnosis; Disease; Disease susceptibility; Education; Elderly; Enrollment; Ethnic Population; European ancestry; Family; Family Study; Family member; Frequencies; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genomics; Geographic Locations; Goals; Heritability; Heterogeneity; High Prevalence; Individual; Induced pluripotent stem cell derived neurons; Measures; Microglia; Molecular; Neurocognitive; Neuropsychology; Not Hispanic or Latino; Pattern; Phenotype; Plasma; Population; Prevention; Prevention strategy; Research Design; Risk; Role; Rural Community; Sample Size; Sampling; Testing; Tissue Donations; Trust; Underrepresented Populations; Underserved Population; Urban Community; Variant; brain tissue; cohort; data integration; design; disease phenotype; druggable target; epigenomics; gene discovery; genetic architecture; genetic risk factor; genome sequencing; genome wide association study; health data; improved; induced pluripotent stem cell; interest; novel; phenotypic data; precision medicine; programs; protective factors; racial population; rare variant; risk prediction; risk variant; social health determinants; tool; transcriptomics; whole genome

ABSTRACT The goal of this proposal is to advance our understanding of the genetic etiology of Alzheimer disease (AD) risk in understudied and underserved populations. AD is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups, but most genetic studies for AD have been performed in non-Hispanic Whites (NHW) of European ancestry. This is problematic, as much smaller studies in African Americans (AA), who have a higher prevalence of AD compared to NHW, have already revealed differences in risk effect sizes in known loci (e.g., APOE; ABCA7), indicating multiple unique patterns of risk. Genetic ancestry (including variability in allele risk frequencies and population specific variants modifying known and novel risk loci), in addition to environmental/cultural factors and their interactions with genetic risk, likely underlies part of this heterogeneity. With only a small number of the whole genome sequences in the Alzheimer’s Disease Sequencing Project (ADSP) coming from AA, increased sample sizes and multiple study designs are needed to elucidate risk in diverse ancestral populations. Family studies provide a powerful complementary design to case- control studies that can enhance risk prediction and the detection of novel rare risk variants. Filling these critical gaps using genetic tools will enhance our understanding of AD risk and provide the basis for identifying prevention strategies and druggable targets. Including ancestral populations from Africa in particular a unique cohort of multiplex African AD families enables dissecting risk not only in African populations but also among all populations with AF ancestry. Our efforts will allow for improved disease prediction, prevention, diagnosis, and treatment through precision medicine, in AA, African, and other African admixed populations.

摘要 这项提案的目的是推进我们对阿尔茨海默病遗传病因学的理解 (AD)研究不足和服务不足人群的风险。AD是老年痴呆症的主要原因 并且发生在所有种族和种族群体中，但大多数AD遗传研究都是在非西班牙裔中进行的。 欧洲血统的白人（NHW）。这是有问题的，因为在非洲裔美国人（AA）中进行的小得多的研究， 与NHW相比，AD患病率更高的人，已经揭示了风险效应大小的差异， 已知的基因座（例如，APOE; ABCA 7），表明多种独特的风险模式。遗传学（包括 等位基因风险频率的变异性和修饰已知和新风险基因座的群体特异性变体）， 除了环境/文化因素及其与遗传风险的相互作用外， 异质性只有一小部分阿尔茨海默氏症的全基因组序列 由于测序项目（ADSP）来自AA，因此需要增加样本量和多种研究设计， 阐明不同祖先群体的风险。家庭研究提供了一个强大的补充设计的情况下- 对照研究可以增强风险预测和检测新的罕见风险变异。填补这些关键 使用遗传工具的差距将增强我们对AD风险的理解，并为识别 预防策略和药物目标。包括来自非洲的祖先， 多重非洲AD家族队列不仅可以在非洲人群中，而且可以在所有人群中进行解剖风险 有AF祖先的人群。我们的努力将有助于改善疾病的预测、预防、诊断， 通过精准医疗，在AA，非洲和其他非洲混合人群中进行治疗。