Use of hormone replacement therapy (HRT) appears to protect some women from Alzheimer's disease, according to a prospective observational study of AD risk factors published in this week's JAMA. In particular, the study found that while prior use of HRT was protective, current use was only protective if it exceeded 10 years, supporting the hypothesis that there is a critical window in which HRT can protect against AD.

Although the media sounded a death knell for HRT following the recent termination of the Women's Health Initiative trial of estrogen with progestin (see related news story), the Alzheimer’s research community is still awaiting the results of a number of observational and intervention studies of hormones and AD. Among the ongoing randomized clinical trials of estrogen (without progestin) are the Women's Health Initiative Memory Study (WHIMS), the Women's International Study of Long Duration Oestrogen after Menopause (WISDOM), and the PREventing Postmenopausal Memory Loss and Alzheimer's with Replacement Estrogens (PREPARE) trial.

Among the data that will have to be considered in justifying continued intervention studies is the present report by John Breitner, Peter Zandi, and colleagues from the University of Washington in Seattle, Johns Hopkins University in Baltimore, Maryland, and other institutions. Their Cache County (Utah) Study is a longitudinal study of risk factors for AD and other dementias. (Publications to date include Zandi et al., 2002; Tschanz et al., 2002; Miech et al., 2002; and Breitner et al., 1999). They now report on the incidence of dementia among the 1,357 men (mean age 73.2 years) and 1,889 women (mean age 74.5 years) in the study at the first three-year follow-up. This is not a definitive study. Only a small number of people had developed AD by this follow-up point, and findings from observational studies are sometimes overturned by later trials.

As in several of the landmark prospective estrogen/AD epidemiologic studies (Tang et al., 1996; Kawas et al., 1997), the risk of incident AD among women who had ever used HRT was reduced to about half that of non-users. Longer duration of HRT use especially reduced AD risk; with 10+ years of HRT use, the risk for women dropped to a significantly lower level than that of the men in the study.

To try to control for healthier behavior by HRT users, the authors examined the use of multivitamin and calcium supplements, and found these not to reduce the risk of incident AD. A new finding was an apparent limited time window for the beneficial effects of HRT use on AD. Whereas former use of HRT greatly reduced the risk of AD, current use only did so if taken for longer than 10 years. "The results with both HRT and NSAIDs suggest that potentially neuroprotective agents may be useful only in the latent pathogenic stages of AD, before there is extensive damage to the integrity of the brain," write the authors.

In an editorial, Susan Resnick of the National Institute on Aging, in Bethesda, Maryland, and Victor Henderson of the University of Arkansas, Little Rock, note that this has implications for trials such as WHIMS, WISDOM, and PREPARE, all of which involve women who began HRT after age 65. "The results … offer both hope for a possible neuroprotective effect of hormone therapy and frustration that it could be difficult to determine the optimal timing of treatment," they write. However, they also point out that "almost all hormone use in this cohort involved estrogen treatment unopposed by progestin, which may offer the greatest potential for neuroprotection."—Hakon Heimer


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News Citations

  1. Safety Concerns Derail Estrogen/Progestin Trial

Paper Citations

  1. . Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology. 2002 Sep 24;59(6):880-6. PubMed.
  2. . An adaptation of the modified mini-mental state examination: analysis of demographic influences and normative data: the cache county study. Neuropsychiatry Neuropsychol Behav Neurol. 2002 Mar;15(1):28-38. PubMed.
  3. . Incidence of AD may decline in the early 90s for men, later for women: The Cache County study. Neurology. 2002 Jan 22;58(2):209-18. PubMed.
  4. . APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study. Neurology. 1999 Jul;53(2):321-31.
  5. . Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet. 1996 Aug 17;348(9025):429-32. PubMed.
  6. . A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology. 1997 Jun;48(6):1517-21. PubMed.

Further Reading


  1. . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. PubMed.

Primary Papers

  1. . Hormone therapy and risk of Alzheimer disease: a critical time. JAMA. 2002 Nov 6;288(17):2170-2. PubMed.