ALZ/OBSERVE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 雌激素阿尔茨海默病预防试验旨在测试激素替代疗法在延缓有阿尔茨海默病家族病史的65岁以上女性阿尔茨海默病(AD)发病和记忆力丧失方面的安全性和有效性。最初的资助方案是随机、双盲安慰剂对照平行分组设计，按子宫切除状况和地理中心分层；研究药物为倍美力(0.625 mg)或倍美力(0.625 mg倍美力加2.5mg醋甲羟孕酮)，用于子宫完整的患者。如下所述，2003年5月发表的妇女健康倡议记忆研究(WHIMS)的研究结果要求对使用雌激素的AD Prevential试验的方案和研究设计进行修改。 目标 根据观察性研究和实验室得出的数据，我们假设口服雌激素(单独或与孕酮联合使用)将显著降低一级亲属(即父母、兄弟姐妹、孩子或大家庭成员，如果这些信息因过早死亡而未知)中有AD家族史的女性患AD的风险。我们还假设，随着时间的推移，服用口服雌激素的女性在记忆任务中的表现将比服用安慰剂的女性更好。为了研究这些假设，我们建议跟踪350名年龄在65岁及以上的女性的队列，她们是健康的，没有痴呆，但有一级亲属(或如果一级亲属由于过早死亡而不知道这些信息，则为大家庭成员)有AD家族史。所有参与者之前都参加了阿尔茨海默病预防试验，他们被随机分为普瑞普罗或安慰剂。具体目标是： 1.比较随机服用雌激素或安慰剂的女性中临床诊断为可能或可能的AD的5年累积发病率； 2.比较服用雌激素或安慰剂的妇女的5年累积不良反应发生率，比较所有原因死亡率，并检查服用活性药物和安慰剂的妇女的耐受性。 此外，我们建议审查四个领域的次要结果衡量。这些领域包括生物领域、功能领域、情感领域和其他认知领域。 研究设计 概述：约350名先前参加过阿尔茨海默病预防试验并随机服用Prempro或安慰剂的健康、未切除子宫的妇女将在一项观察性研究中接受跟踪观察。所有参与者都是非痴呆者，女性，65岁或以上，有AD家族史。附录中提供了一张表格，说明每次查访所完成的程序。主要结果指标将包括偶发痴呆症和记忆力下降。参与者将接受为期5年(60个月)的跟踪调查，并将每隔6个月进行一次检查，以评估依从性、不良事件和一般健康状况。在随访期间，将进行年度内科、妇科、神经心理和功能评估。在每一次年度评估中，都会确定是否有足够的认知变化来触发“痴呆症评估”。如果触发，评估将在年度评估后一个月内进行。所有参与者将在5年后接受评估。每个痴呆症评估的结果将在协商一致的会议上进行审查，以确定AD事件的主要结果。我们将使用意向治疗分析。分析将把对立和非对立的雌激素治疗合并为一组，并将它们与安慰剂进行比较。载脂蛋白E基因、文化程度和民族是二次分析的潜在协变量。安全评估将基于年度评估和报告的不良事件的结果。患有痴呆症的参与者将被告知标准治疗，并将在研究期间继续每年一次的跟踪观察。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Alzheimer's Disease Prevention Trial with Estrogens was designed to test the safety and efficacy of hormone replacement therapy in delaying the onset of Alzheimer's disease (AD) and memory loss in women over age 65 who have a family history of AD. As originally funded, the protocol was randomized, double blind placebo controlled parallel group design with stratification by hysterectomy status and geographic center; study medication was Premarin (0.625mg) or Prempro (0.625 mg Premarin plus 2.5 mg medroxyprogesterone acetate) for those who had an intact uterus. As described below, findings published in May 2003 from the Women's Health Initiative Memory Study (WHIMS) necessitated changes to the protocol and study design of the AD Prevential Trial with Estrogens. Objectives Based on data accrued from observatinal studies, and that derived in the laboratory, we hypothesize that oral estrogens (alone or in combination with progesterone) will significantly reduce the risk of AD among women with a family history of AD in a first-degree relative (i.e., parent, sibling, child, or an extended family member if such information is unknown in first-degree relative due to early death). We also hypothesize that women who use oral estrogen will have better performance on memory tasks over time compared to women on placebo. To study these hypotheseses, we propose to follow a cohort of 350 women, age 65 and older, who are healthy and not demented, but who have a family history of AD in a first degree relative (or an extended family member if such information is unknown in a first degree relative due to early death). All participants were previously enrolled in the Alzheimer's Disease Prvention Trial where they were randomized to either PremPro or placebo. The specific aims are to: 1. compare the 5-year cumulative incidence rate of clinically diagnosed probable or possible AD among women randomized to either estrogens or placebo; 2. compare the 5-year cumulative incidence rates of adverse effects and compare all cause mortality among women randomized to either estrogens, or placebo and examine tolerability among women on active drug and placebo. In addition we propose to examine 4 domains of secondary outcome measures. These include biological, functional, affective, and other cognitive domains. Study Design Overview: Approximately 350 healthy, non-hysterectomized women who were previously enrolled in the Alzheimer's Disease Prevention Trial and randomized to either PremPro or placebo will be folloed in an observational study. All participants are non-demented, women, 65 years of age or older, with a family history of AD. A table describing the procedures completed at each visit is provdied in the appendix. The primary outcome measures will include incident dementia and memory decline. Participants will be followed over a 5 year (60 months) period, and will be examined at 6 month intervals to assess compliance, adverse events and general health status. Annual medical, gynecological, neuropsychological and functional assessemtns will occur during follow-up. At each annual evaluation, it will be determined if there is sufficient cognitive change to trigger a "dementia evaluation". If triggered the evaluation will occur within one month of the annual assessment. All participants will receieve the evaluation at the end of 5 years. The results of each dementia evaluation will be reviewed at a consensus conference to determine the primary outcome of incident AD. We will use an intent-to-treat analysis. Analyses will combine opposed and unopposed estrogens treatments into a single group and compare them to placebo. APOE genotype, educational level and ethnic group are potential covariates for the secondary analyses. Safety evaluations will be based on findings from annual assessments and reported adverse events. Partcipants who become demented will be informaed of standard-of-care treatment and will continue to be followed at annual intervals for the length of the study.