Statin Treatment and Incident Alzheimer's Disease and Related Dementias in a Large, Multi-ethnic Health Plan

项目总结/摘要 数以百万计的中年和老年人正在使用他汀类药物，尽管已经给予了关注， 他汀类药物治疗可能降低阿尔茨海默病和相关痴呆症（ADRD）的风险， 他汀类药物的这种益处存在很大的不确定性， 对认知功能的影响即使ADRD风险的微小益处或危害也可能对公共健康产生重大影响 重要性，但以前的研究还没有获得足够大的队列详细的协变量数据， 提供精确的估计，完全控制指示或其他内部有效性威胁的混淆。 该项目使用Kaiser Permanente北方的综合电子健康记录（EHR 加州对超过100万年龄在65岁及以上的人（34%的他汀类药物使用者）进行了多元化、多种族的队列研究， 实验室指标（包括LDL胆固醇）和相关临床状况的纵向数据，以及 一项对254，000人的调查提供了额外的社会经济和行为风险因素数据。这些数据资源 联合收割机将大型管理纵向数据集的优点与详细实验室的优点结合起来， 药物学和协变量控制。有了这些数据，我们将能够评估（AIM 1）启动的净效应 他汀类药物对ADRD风险的影响以及他汀类药物的作用是否取决于类型、时间、持续时间或剂量。这些 都是容易修改的因素，对它们潜在的好处或危害的精确估计将直接影响到我们的生活。 临床相关性我们还将评估（AIM 2）效果是否因社会、人口统计学、临床或 遗传背景KPNC的成员是非常种族/民族多样化，所以我们将能够 提供严格的测试，以确定对非裔美国人、拉丁美洲人、亚裔美国人或非拉丁美洲人的影响是否不同。 白人超过67，000名参与者的遗传信息可供评估， ADRD遗传风险因素或与血脂反应和心血管疾病相关的遗传变异改变了 他汀类药物对ADRD的影响。最后，我们将评估（AIM 3）他汀类药物是否通过改变ADRD风险 LDL水平，诊断为脑血管或心血管疾病，或通过其他机制。如果是这样， 未来研究如何利用这些不同机制的途径，无论是他汀类药物还是潜在的 通过其他药物治疗或干预。这些目标是独立的必要帮助解释 他汀类药物和痴呆症的先前研究结果不一致。研究小组聚集在一起， 这些目标包括所有数据源、他汀类药物、药物流行病学、统计遗传学和 ADRD研究的流行病学方法。他汀类药物可能被明智地应用于减少 ADRD的终生风险将影响目前使用他汀类药物的指南， 制定ADRD的人口预防战略。主要KPNC队列和相关调查和遗传数据 提供无与伦比的资源。在缺乏超大型随机对照试验的情况下，拟议的研究将提供 他汀类药物对ADRD影响的最确凿证据。

Project Summary/ Abstract Millions of middle-aged and older adults are using statins, and despite the attention that has been given to the possibility that statin treatment may reduce risk of Alzheimer’s Disease and Related Dementias (ADRD), there is substantial uncertainty about such a benefit, as well as concern regarding possible adverse effects of statins on cognitive function. Even a small benefit or harm for ADRD risk could be of substantial public health importance, but prior research has not had access to sufficiently large cohorts with detailed covariate data to provide precise estimates with full control for confounding by indication or other threats to internal validity. This project uses the comprehensive electronic health records (EHRs) of Kaiser Permanente Northern California on a diverse, multi-ethnic cohort of over 1 million individuals age 65 and over (34% statin users), with longitudinal data on laboratory measures (including LDL cholesterol) and related clinical conditions, and a survey of 254,000 providing additional socioeconomic and behavioral risk factor data. These data resources combine the advantages of both a large administrative longitudinal data set with the advantages of detailed lab, pharmacy, and covariate control. With these data we will be able to evaluate (AIM 1) the net effect of initiating statins on the risk of ADRD and whether the effects of statins depend on type, timing, duration, or dose. These are all easily modified factors and precise estimates of their potential benefit or harm would have immediate clinical relevance. We will also evaluate (AIM 2) whether effects differ based on social, demographic, clinical, or genetic background. The KPNC membership is exceptionally racially/ethnically diverse, so we will be able to provide rigorous tests of whether effects differ for African Americans, Latinos, Asian Americans, or non-Latino Whites. Genetic information is available for over 67,000 participants, permitting evaluation of whether major ADRD genetic risk factors or genetic variants related to lipid response and cardiovascular disease modify the effects of statins on ADRD. Finally, we will evaluate (AIM 3) whether statins influence ADRD risk via changes in LDL levels, diagnosed cerebrovascular or cardiovascular disease, or via other mechanisms. If so, this opens the path for future research on how to leverage these different mechanisms, either with statins or potentially via other pharmacotherapies or interventions. These aims are independently essential to help explain inconsistent results from prior research on statins and dementia. The research team assembled to accomplish these aims includes expertise on all the data sources, statins, pharmacoepidemiology, statistical genetics, and epidemiologic methods for study of ADRD. The possibility that statins might be judiciously applied to reduce lifetime risk of ADRD would impact current guidelines for use of statins and would be a powerful advance towards a population prevention strategy for ADRD. The main KPNC cohort and linked survey and genetic data provide an unparalleled resource. In the absence of extremely large RCTs, the proposed research will provide the most conclusive evidence for the effects of statins on ADRD.