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年将增加一倍，到2050年将增加两倍。AD仍然无法治愈，ADRD的原因 在很大程度上仍然未知，但它们与许多风险因素有关，包括年龄，教育， 精神障碍、头部创伤和血管疾病或相关危险因素。最近，抗高血压药物 和抗糖尿病药物治疗与较低的患痴呆症的风险有关， 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 降低了轻度认知障碍的风险，并且是第一个证明了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的高发病率， 在成年人群中，使用疾病修饰药物可能为预防提供有效策略 的ADRD。然而，目前还没有大型队列研究监测和评估抗高血压药物的联合作用， 抗糖尿病和抗癌药物对ADRD风险的影响。医疗保险覆盖了大量人口， 自1965年以来，美国65岁或以上的老年人，可使用全面且记录良好的电子数据库 自1991年以来（包括抗癌化疗），提供了一个很好的机会和资源，以监测 ADRD随时间的患病率和发病率。此外，由于Medicare Part-D全面的药物覆盖范围 在2006年实施，有可能确定抗高血压和抗糖尿病药物对 痴呆症的风险。因此，这项拟议研究的主要目标是检验假设， 抗癌、抗高血压和抗糖尿病药物治疗影响了 在过去的30年里，ADRD。为达致这个目标，我们建议达致以下具体目标： 确定1991年至2020年老年人医疗保险受益人中ADRD患病率的长期趋势 美国65岁或以上的患者，以及各州、地理区域、年龄、 性别、人种/种族和合并症; 2）确定与下列因素相关的ADRD发生率： 无痴呆症的医疗保险受益人中的血管因素和其他潜在风险因素， 基线并随访长达30年; 3）确定癌症诊断与 抗癌药物治疗和发生ADRD的风险，通过比较一个大型队列的患者诊断 在1991-2020年期间，将患有主要癌症的人与具有类似背景风险但没有癌症的人进行比较;以及4）确定 抗高血压、抗糖尿病和抗癌药物治疗对以下风险的独立和联合作用： 2007-2020年，在Medicare Part-D之后，65岁或以上的Medicare受益人中发生ADRD 获得了全面的药物数据。这项研究的结果将对以下方面产生重大影响： 预防或延迟ADRD的发作，因此将为初步研究做出实质性贡献 到2025年，国家阿尔茨海默病项目法案的目标。

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.