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Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study
Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E et al.. JAMA, 2000-02-01
Topic: Amyloid, tau and blood-test diagnosis
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.
Key findings
- 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.
- 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).
Why it matters
In this trial of 120 women with mild to moderate Alzheimer disease, estrogen replacement therapy did not significantly differ from placebo on the primary global measure, and 80% of those taking estrogen worsened compared with 74% taking placebo. Secondary measures also showed no significant differences, except the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen.
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Study details
- Participants42
- Effect sizeor 1.25
- Evidence strengthHigh
How this study scored 67/100
Published in a top-tier journal. Scored zero for study design because the record does not state it. We have no data on journal's citation record, so that was left out: it earned 64 of the 96 points we could judge it on, which is 67 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (JAMA) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2000 — older than 20 years, still counted |
| Sample size | 1 / 4 | 42 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 2 / 2 | Randomised and blinded or placebo-controlled (as stated in the record) |
| Times cited | 6 / 7 | Cited 993 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 35.5 citations a year over 28 year(s) since 2000 |
| Impact for its field and year | 6 / 6 | Cited 95.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 29 other studies in this library |
| Still being cited | 2 / 4 | Cited 26 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Leon J. Thal: h-index 90 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Johns Hopkins University: institution h-index 2,306 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 10697060) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 64 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 64 of the 96 points we could judge it on is 67 out of 100. |
| Total | 67 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — Unpaywall lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Mulnard, R. A., Cotman, C. W., Kawas, C., van Dyck, C. H., Sano, M., Doody, R., et al. (2000). Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. https://doi.org/10.1001/jama.283.8.1007
Vancouver
Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000. doi:10.1001/jama.283.8.1007. PMID: 10697060.
BibTeX
@article{mulnard2000-10697060,
author = {Mulnard, R. A. and Cotman, C. W. and Kawas, C. and van Dyck, C. H. and Sano, M. and Doody, R. and Koss, E. and Pfeiffer, E. and others},
title = {{Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study}},
journal = {JAMA},
year = {2000},
doi = {10.1001/jama.283.8.1007},
pmid = {10697060},
url = {https://doi.org/10.1001/jama.283.8.1007}
}
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