Midlife statin use and late life cognition

项目总结/摘要 在美国，观察到阿尔茨海默病和相关痴呆症（ADRD）的发病率下降， 欧洲在过去几十年的研究表明，风险因素的改变可以预防或延迟ADRD。然而，在这方面， 由于发病率下降的确切原因尚不清楚， 随着全球人口老龄化，预计将增长，因此迫切需要确定哪些ADRD 应促进减少风险战略。虽然总胆固醇和低密度脂蛋白升高 胆固醇（LDL-c）与ADRD风险增加相关，目前尚不清楚中年是否 使用他汀类药物是一种有效的ADRD风险降低策略。这在很大程度上是由于推出的时机， 他汀类药物，这是首次批准用于临床使用在20世纪80年代后期;第一组中年他汀类药物使用者有 只是现在已经足够老，有严重的ADRD风险。因此，本提案的总体目标是 调查中年他汀类药物使用是否降低痴呆风险或减缓认知能力下降。为此，我们 建议使用社区动脉粥样硬化风险纵向研究（ARIC）的数据。ARIC参与者 20世纪80年代末入组中年，最近一次研究访问于2018-2019年完成。鉴于 ARIC最初的重点是心血管健康，重点转移到认知健康和痴呆症， ARIC在老年人队列中有关于他汀类药物使用适应症、他汀类药物使用和晚年认知的可靠数据。因此 ARIC数据和数据收集的时间非常适合我们的目标，我们建议使用倾向 评分匹配法评估中年他汀类药物治疗对ADRD事件风险和认知功能的影响 在20年的随访中下降。这种方法解决了现有文献的局限性。之前 研究主要集中在晚年他汀类药物的使用或随访有限。这些研究不会 预计会发现大量的认知益处，因为晚年血脂升高与 痴呆症的风险增加，研究尚未证明使用他汀类药物的近期认知益处。到 相反，我们对中年他汀类药物使用的关注自然来自于与中年血脂升高有关的发现。 水平，以增加认知能力下降和痴呆症的风险，并尽量减少对反向因果关系的担忧。 我们的倾向评分匹配方法和重点治疗的效果，在治疗也明确 识别并设计用于解决指示混淆。中年他汀类药物用于 晚年认知是不道德的，也是不可行的，因为需要很长的随访时间。因此，小心 使用因果推理框架来指导分析的观察数据评估-我们建议 需要提供证据支持或反对中年他汀类药物使用对晚年的因果影响， 认知健康最终，我们的结果将帮助公共卫生专业人员，临床医生和倡导者 确定促进中年他汀类药物用于血脂管理是否合理， 降低ADRD风险。

PROJECT SUMMARY/ABSTRACT The observed decline in the incidence of Alzheimer’s Disease and Related Dementias (ADRD) in the U.S. and Europe over the past few decades suggests that risk factor modification can prevent or delay ADRD. However, as the exact causes of this reduction in incidence remain unclear and the number of people affected by ADRD is large and is expected to grow as the global population ages, there is a critical need to identify which ADRD risk reduction strategies should be promoted. Although elevated total cholesterol and low-density lipoprotein cholesterol (LDL-c) in midlife are associated with increased risk of ADRD, it remains unclear whether midlife statin use is an effective ADRD risk reduction strategy. This is largely due to the timing of the introduction of statins, which were first approved for clinical use in the late 1980s; the first group of midlife statin users have only now aged sufficiently to be at substantial risk of ADRD. Thus, the overall objective of this proposal is to investigate whether midlife statin use reduces risk of dementia or slows cognitive decline. To do so, we propose to use data from the longitudinal Atherosclerosis Risk in Communities (ARIC) study. ARIC participants enrolled in midlife in the late 1980s, with the most recent study visit completed in 2018-2019. Given that the initial focus of ARIC was on cardiovascular health, and the focus shifted to cognitive health and dementia as the cohort aged, ARIC has robust data on indications for statin use, statin use, and late-life cognition. Thus, the ARIC data and timing of data collection are perfectly suited to our aims, and we propose to use a propensity score matching approach to estimate the effect of midlife statin initiation on risk of incident ADRD and cognitive decline over two decades of follow-up. This approach addresses limitations of the existing literature. Prior studies have largely focused on late-life statin use or have limited follow-up. These studies would not be expected to find substantial cognitive benefits because elevated lipids in late-life are not associated with increased risk of dementia, and studies have not demonstrated near-term cognitive benefits of statin use. To the contrary, our focus on midlife statin use follows naturally from findings linking elevated midlife blood lipid levels to increased risk of cognitive decline and dementia, and minimizes concerns about reverse causation. Our propensity-score matching approach and focus on the effect of treatment in the treated also explicitly recognizes and is designed to address confounding by indication. Randomized trials of midlife statin use on late-life cognition are unethical and infeasible due to the required length of follow-up. As such, careful evaluation of observational data using a causal inference framework to guide analyses – which we propose here – will be needed to provide evidence for or against a causal effect of midlife statin use on late-life cognitive health. Ultimately, our results will help public health professionals, clinicians, and advocates determine whether it is reasonable to promote midlife statin use for lipid management as also maintaining brain health and reducing risk of ADRD.