This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
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Special Emphasis Panel (ZRR1-CR-8 (02))
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Howard University
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