The Origins of Alzheimer Disease in African Americans

摘要 这项建议的目的是促进我们对阿尔茨海默病的遗传病因的理解 (Ad)未得到充分研究和服务的人群中的风险。AD是导致老年人痴呆的主要原因 它发生在所有民族和种族群体中，但大多数AD的基因研究都是在非西班牙裔美国人中进行的 欧洲血统的白人。这是有问题的，因为对非裔美国人(AA)的研究要小得多， 与NHW相比，AD患病率更高的人，已经显示出风险效应大小在 已知的基因座(例如，APOE；ABCA7)，表明多种独特的风险模式。遗传血统(包括 等位基因风险频率的变异性和修改已知和新风险基因的群体特定变异)，在 除了环境/文化因素及其与遗传风险的相互作用外，这可能是部分原因 异质性。只有一小部分阿尔茨海默病的全基因组序列 来自AA的测序项目(ADSP)，需要增加样本量和多项研究设计来 阐明不同祖先群体中的风险。家庭研究为病例提供了强大的补充设计- 可加强风险预测和检测新的罕见风险变种的对照研究。填写这些关键信息 使用基因工具的差距将增强我们对AD风险的理解，并为识别 预防战略和可用药目标。包括来自非洲的祖先人口，特别是一个独特的 非洲多个AD家族的队列不仅可以在非洲人群中剖析风险，也可以在所有人中剖析风险 有房颤血统的人群。我们的努力将允许改进疾病预测、预防、诊断和 在再生障碍性贫血、非洲和其他非洲混合人群中通过精准医学进行治疗。

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.