Dementia prevalence, APOE, and blood-based biomarkers of AD in Native American communities

项目摘要/摘要 痴呆症领域正在取得重大进展。有症状的阿尔茨海默病(AD)可以是 通过一次简单的验血确诊。人均新增痴呆症患者的数量正在减少，与 旨在改善大脑健康的公共卫生运动。新的药物正在涌现，它们承诺有效地预防或 治疗痴呆症。虽然这些在痴呆诊断、预防和治疗方面的突破是 值得庆祝的是，几乎没有人知道这些进步是否会转化为土著 美国(NA)社区，从生物医学的角度对痴呆症知之甚少。为 例如，在撰写本文时，只有两个NA在AD神经成像中有可用的血液测试数据 倡议，美国最大的AD生物库。大约200个NA已经包括在最大的 在该国40,000多名参与者中，有一个广告财团。在北卡罗来纳州缺乏关于痴呆症的知识 这是有问题的，并预示着本已严重的健康差距将进一步扩大。当前研究的中心是 假设美国印第安人有独特的痴呆症危险因素和载脂蛋白Eε4的不同影响- 阿尔茨海默病最显著的遗传危险因素。这些因素将改变痴呆症的流行病学， 排除使用APOEε4进行“一刀切”的AD血液测试，当前项目的第一个目标是确定 NA部落民族中存在哪些类型的痴呆症，目前尚不清楚，但这是迈向 设计和实施有效的脑健康政策。第二个目标涉及测量祖先-- 在NA中，载脂蛋白E对AD风险和AD生物学的依赖作用。AD血液测试利用载脂蛋白E基因和 直接对与AD相关的毒性蛋白进行定量，以确定阳性或阴性结果。如果 遗传自欧洲祖先，具有载脂蛋白Eε4等位基因会增加患AD的几率，而且 增加AD血液检测结果呈阳性的可能性。但如果患者的载脂蛋白Eε4基因是从 非洲祖先，对定义阿尔茨海默病的有毒蛋白质的积累有减弱的影响。相同 APOEε4和AD之间的中性关系可能适用于我们小组的NA初步数据和 其他人则认为，从NA祖先那里继承载脂蛋白Eε4基因同样不会增加AD的风险。 如果安娜个人接受AD血液检测，并携带载脂蛋白Eε4等位基因，他们会得到改变人生的机会吗 但对毁灭性疾病的错误诊断呢？因此，我们的研究将衡量APOE与 和北卡罗来纳州的AD风险/生物学。由于APOE也是个性化医疗的核心内容，因此风险/收益讨论 对于抗淀粉样蛋白治疗、试验资格和基因引导治疗的靶点，这项研究将提供 关于基于APOE的医学进展对NA的适用性的关键知识。这是我们的第一个研究 试图将美国印第安人痴呆症护理带入21世纪并提供 为这一未充分研究的群体奠定基础，使其受益于诊断、预防和治疗方面的最新进展 痴呆症。

PROJECT SUMMARY/ABSTRACT Great advances are underway in the field of dementia. Symptomatic Alzheimer’s’ disease (AD) can be diagnosed with a simple blood test. The number of new dementia patients per capita is shrinking in parallel to public health campaigns to improve brain health. New drugs are emerging that promise to effectively prevent or treat dementing illness. While these breakthroughs in dementia diagnostics, prevention and treatment are cause for celebration, hardly anything is known about whether these advances will translate to Native American (NA) communities, where very little is known about dementia from a biomedical perspective. For instance, only two NA at the time of this writing have available blood test data in the AD Neuroimaging Initiative, the largest AD biobank in the United States. Approximately 200 NA have been included in the largest AD consortium in the country out of over 40,000 participants. This lack of knowledge regarding dementia in NA is problematic and portends a widening of already severe health disparities. The current study’s central hypothesis is that American Indians have unique dementia risk factors and a differential effect of APOE ε4 – the most significant genetic risk factor for AD. These factors will change the epidemiology of dementia and preclude a “one size fits all” AD blood test using APOE ε4, The first goal of the current project is to determine what types of dementia exist among NA Tribal Nations, which is currently unknown but is a first-step to designing and implementing effective brain health policy. The second goal involves measuring the ancestry- dependent effect of APOE on AD risk and AD biology in NA. AD blood tests utilize the APOE gene along with direct quantification of the toxic proteins associated with AD to determine a positive or negative result. If inherited from a European ancestor, having an APOE ε4 allele increases the chances of AD and also increases the probability of a positive AD blood test result. But if a patient inherits their APOE ε4 gene from an African ancestor, there is an attenuated impact on accumulation of toxic proteins that define AD. The same neutral relationship between APOE ε4 and AD likely applies to NA – preliminary data from our group and others suggest that inheriting an APOE ε4 gene from a NA ancestor similarly does not increase the risk of AD. If an NA individual undergoes an AD blood test and carries an APOE ε4 allele, will they receive a life-changing but false diagnosis for a devastating condition? Our study thus will measure the relationship between APOE and AD risk/biology in NA. As APOE is also a centerpiece of personalized medicine, risk/benefit discussions for anti-amyloid therapy, trial eligibility, and the target of genetically guided therapies, this study will provide critical knowledge about the applicability of APOE based medical advances to NA. This is the first study to our knowledge that attempts to bring American Indian dementia care into the 21st century and provide a foundation for this understudied group to benefit from the latest advances in diagnosis, prevention treatment of dementia.