Midlife statin use and late life cognition

项目摘要/摘要 据观察，美国阿尔茨海默病和相关痴呆症(ADRD)的发病率下降 欧洲过去几十年的经验表明，修改风险因素可以预防或推迟ADRD。然而， 由于发病率下降的确切原因尚不清楚，受ADRD影响的人数 是巨大的，预计随着全球人口老龄化而增长，迫切需要确定哪一种ADRD 应推广降低风险战略。尽管总胆固醇和低密度脂蛋白升高 中年的胆固醇(ldl-c)与ADRD的风险增加有关，目前尚不清楚中年是否 他汀类药物的使用是降低ADRD风险的有效策略。这在很大程度上是由于引入 他汀类药物，在20世纪80年代末首次被批准用于临床；第一批中年他汀类药物使用者 只是现在年龄足够大，有患ADRD的巨大风险。因此，这项提案的总体目标是 研究中年使用他汀类药物是否会降低患痴呆症的风险或减缓认知能力的下降。为了做到这一点，我们 建议使用社区纵向动脉粥样硬化风险(ARIC)研究的数据。ARIC参与者 20世纪80年代末注册进入中年，最近一次学习访问于2018-2019年完成。考虑到 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，因为 在年龄较大的ARIC中，有关于他汀类药物使用、他汀类药物使用和晚年认知的迹象的可靠数据。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开始应用他汀类药物对ADRD和认知风险的影响 在二十多年的随访中有所下降。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上，或者随访有限。这些研究不会是 有望发现实质性的认知益处，因为晚年的高血脂与 增加痴呆症的风险，而且研究还没有证明使用他汀类药物对认知的近期好处。至 相反，我们对中年他汀类药物使用的关注自然源于发现中年血脂升高 水平，以增加认知能力下降和痴呆症的风险，并最大限度地减少对反向因果关系的担忧。 我们的倾向性评分匹配方法和注重疗效的治疗在治疗中也是明确的 识别并旨在通过指示解决混淆问题。中年使用他汀类药物的随机试验 晚年认知是不道德的，也是不可行的，因为需要长时间的随访。因此，要小心 使用因果推理框架来指导分析--这是我们建议的--对观测数据的评估 在这里-将需要提供证据支持或反对中年使用他汀类药物对晚年的因果影响 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 确定推广中年他汀类药物用于血脂管理和维护大脑是否合理 健康和降低ADRD的风险。

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.