The Risk of Developing Alzheimer's Disease and Related Dementias Associated with Hypertension, Diabetes, and Drug Therapies for Cancer: Up to 30-year Follow-up for Older Medicare Beneficiaries

摘要 阿尔茨海默病(AD)和相关痴呆(ADRD)的患病率在过去一直在增加 预计到2025年将翻一番，到2050年将翻两番。AD仍然不治之症，ADRD的原因 在很大程度上仍不清楚，但它们与许多风险因素有关，包括年龄、教育程度、 精神障碍、头部创伤、血管疾病或相关危险因素。最近，抗高血压药物 抗糖尿病药物治疗与患痴呆症的风险较低有关， 认知障碍。2019年，一项大型临床试验报告称，强化血压控制显著 降低轻度认知障碍的风险，是第一个证明有效的治疗策略的试验 预防与年龄相关的认知障碍。鉴于高血压和糖尿病在中国的高患病率 成人人群中，疾病修饰药物的使用可能为预防提供一种有效的策略 是ADRD的。然而，没有大规模的队列研究监测和评估抗高血压的联合作用， 抗糖尿病和抗癌药物对ADRD风险的影响。覆盖了大量人口的医疗保险 自1965年以来在美国65岁或以上的老年人拥有全面和有充分记录的电子数据库 自1991年以来(包括抗癌化疗)，提供了一个很好的机会和资源来监测 随时间推移ADRD的患病率和发病率。此外，由于Medicare Part-D全面的药物覆盖范围 2006年开始实施，有可能确定降压和降糖药物对 这些痴呆症的风险。因此，这项拟议的研究的主要目标是检验以下假设 抗癌、抗高血压和抗糖尿病药物治疗影响了糖尿病的患病率和发病率 ADRD在过去的30年里。为此，我们建议实现以下具体目标：1) 确定1991年至2020年老年医疗保险受益人中ADRD患病率的长期趋势 在美国65岁或以上，ADRD的患病率按州、地理区域、年龄、 性别、种族/民族和共病；2)确定与以下方面有关的ADRD的发生率 未患痴呆症的医疗保险受益人的血管因素和其他潜在危险因素 基线和长达30年的跟踪调查；3)确定癌症诊断和 比较大量确诊患者的抗癌药物治疗与ADRD风险 在1991-2020年间，将主要癌症与具有相似背景风险但未患癌症的人进行比较；以及4)确定 降压、降糖和抗癌药物治疗对高血压风险的独立和联合作用 2007-2020年联邦医疗保险D部分后65岁及以上受益人中ADRD的发展 全面的药物数据变得可用。这项研究的发现将对 预防或推迟ADRD的发生，因此将对初步研究做出实质性贡献 到2025年，国家阿尔茨海默氏症项目法案的目标。

Abstract The prevalence of Alzheimer’s disease (AD) and related dementias (ADRD) has been increasing over the past few decades and is projected to double by 2025 and triple by 2050. AD is still incurable, and causes of ADRD remain largely unknown, but they have been linked to many risk factors, including age, education, history of psychiatric disorders, head trauma, and vascular diseases or related risk factors. More recently, antihypertensive and antidiabetic drug therapies have been associated with a lower risk of developing dementia and early cognitive impairment. In 2019, a large clinical trial reported that intensive blood pressure control significantly reduced the risk of mild cognitive impairment and was the first trial to demonstrate an effective strategy for the prevention of age-related cognitive impairment. Given a high prevalence of hypertension and diabetes in the adult population, the utilization of disease-modifying drugs may provide an effective strategy for the prevention of ADRD. However, there is no large cohort study monitoring and assessing the joint effects of antihypertensive, antidiabetic, and anticancer medications on the risk of ADRD. Medicare, which has covered a large population aged 65 or older in the U.S. since 1965 with comprehensive and well-documented electronic databases available since 1991 (including anticancer chemotherapy), provides a great opportunity and resource to monitor the prevalence and incidence of ADRD over time. In addition, since Medicare Part-D comprehensive drug coverage was implemented in 2006, it is possible to determine the impact of antihypertensive and antidiabetic drugs on the risk of these dementias. Hence, the primary goal of this proposed study is to test the hypothesis that anticancer, antihypertensive and antidiabetic drug therapies have impacted the prevalence and incidence of ADRD over the past 30 years. To accomplish this, we propose to address the following Specific Aims: 1) to determine the secular trends in the prevalence of ADRD from 1991 to 2020 among Medicare beneficiaries aged 65 or older in the United States and variations in the prevalence of ADRD by state, geographic region, age, gender, race/ethnicity, and comorbidity; 2) to determine the incidence of developing ADRD in association with vascular factors and other potential risk factors among Medicare beneficiaries who were free of dementia at baseline and followed for up to 30 years; 3) to determine the association between a cancer diagnosis and anticancer drug therapies and the risk of developing ADRD by comparing a large cohort of patients diagnosed with major cancers to those with similar background risks but without cancer in 1991-2020; and 4) to determine the independent and joint effects of antihypertensive, antidiabetic and anticancer drug therapies on the risk of developing ADRD among Medicare beneficiaries aged 65 or older in 2007-2020 after Medicare Part-D comprehensive drug data became available. The findings from this study will have significant implications for preventing or delaying the onset of ADRD and hence will make substantial contributions to the primary research goal of the National Alzheimer’s Project Act by 2025.