ALZ/OBSERVE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 雌激素预防阿尔茨海默病试验旨在测试激素替代疗法在延迟65岁以上有AD家族史的女性中阿尔茨海默病（AD）和记忆丧失的安全性和有效性。根据最初的资助，该方案是随机、双盲安慰剂对照平行组设计，按子宫切除术状态和地理中心分层;对于子宫完整的患者，研究药物为倍美力（0. 625 mg）或Prempro（0. 625 mg倍美力加2. 5 mg醋酸甲羟孕酮）。如下所述，2003年5月发表的妇女健康倡议记忆研究（WHIMS）的结果需要对雌激素AD预防性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研究数据，我们假设口服雌激素（单独或与孕酮联合）将显著降低一级亲属（即，父母、兄弟姐妹、子女或大家庭成员（如果一级亲属因早逝而不知道这些信息）。我们还假设，与服用安慰剂的女性相比，服用口服雌激素的女性随着时间的推移在记忆任务中的表现会更好。为了研究这些假设，我们建议随访350名年龄在65岁及以上的女性，她们健康且没有痴呆，但在一级亲属中有AD家族史（或大家庭成员，如果一级亲属由于早逝而不知道这些信息）。所有参与者之前都参加了阿尔茨海默病预防试验，在那里他们被随机分配到PremPro或安慰剂组。具体目标是： 1.比较随机接受雌激素或安慰剂治疗的女性中临床诊断为可能或可能AD的5年累积发病率; 2.比较5年累积的不良反应发生率，比较随机分配到雌激素组或安慰剂组的妇女的全因死亡率，并检查活性药物组和安慰剂组妇女的耐受性。 此外，我们建议检查4个领域的次要结果的措施。这些包括生物、功能、情感和其他认知领域。 研究设计 概述：大约350名健康的、未切除子宫的妇女，她们先前参加了阿尔茨海默病预防试验，并随机接受了PremPro或安慰剂，将在一项观察性研究中进行随访。所有参与者均为非痴呆女性，年龄在65岁或以上，有AD家族史。描述每次访视时完成的程序的表格见附录。主要结果指标将包括痴呆和记忆力下降。受试者将接受为期5年（60个月）的随访，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。随访期间将进行年度医学、妇科、神经心理学和功能评估。在每次年度评估中，将确定是否有足够的认知变化来触发“痴呆评估”。如果触发，将在年度评估后一个月内进行评估。所有参与者将在5年结束时接受评估。每次痴呆评估的结果将在共识会议上进行审查，以确定AD事件的主要结局。我们将使用意向治疗分析。分析将结合联合收割机反对和非反对雌激素治疗成一个单一的组，并比较他们与安慰剂。APOE基因型、教育水平和种族是次要分析的潜在协变量。安全性评价将基于年度评估结果和报告的不良事件。将告知患有痴呆症的参与者标准治疗，并在研究期间继续每年随访一次。

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.