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A Randomized Controlled Trial

Ruth A. Mulnard, RN, DNSc; Carl W. Cotman, PhD; Claudia Kawas, MD; Christopher H. van Dyck, MD; Mary Sano, PhD; Rachelle Doody, MD, PhD; Elizabeth Koss, PhD; Eric Pfeiffer, MD; Shelia Jin, MD, MPH; Anthony Gamst, PhD; Michael Grundman, MD, MPH; Ronald Thomas, PhD; Leon J. Thal, MD; for the Alzheimer's Disease Cooperative Study

JAMA. 2000;283:1007-1015.

Context  Several reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women.

Objective  To determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD.

Design  The Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999.

Setting  Thirty-two study sites in the United States.

Participants  A total of 120 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 28 who had had a hysterectomy.

Interventions  Participants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25 mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew after randomization but before receiving medication; 97 subjects completed the trial.

Main Outcome Measures  The primary outcome measure was change on the Clinical Global Impression of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome measures included other global measures as well as measures of mood, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living; compared by the combined estrogen groups vs the placebo group at 2, 6, 12, and 15 months of follow-up.

Results  The CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants taking placebo worsened (P = .48). Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for placebo; P = .01).

Conclusions  Estrogen replacement therapy for 1 year did not slow disease progression nor did it improve global, cognitive, or functional outcomes in women with mild to moderate AD. The study does not support the role of estrogen for the treatment of this disease. The potential role of estrogen in the prevention of AD, however, requires further research.

Author Affiliations: University of California, Irvine (Drs Mulnard and Cotman); Johns Hopkins University, Baltimore, Md (Dr Kawas); Yale University, New Haven, Conn (Dr van Dyck); Columbia University, New York, NY (Dr Sano); Baylor College of Medicine, Houston, Tex (Dr Doody); Case Western Reserve University, Cleveland, Ohio (Dr Koss); University of South Florida, Tampa (Dr Pfeiffer); and the University of California, San Diego (Drs Jin, Gamst, Grundman, Thomas, and Thal).

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