Memory or Mammaries? The Controversy about HRT Continues . . .

Abstract & Commentary

Synopsis: Long-term and prior hormone replacement therapy (HRT) is associated with a reduced risk of Alzheimer’s disease.

Source: Zandi PP, et al, for the Cache County Memory Study Investigators. Hormone replacement therapy and incidence of Alzheimer disease in older women. JAMA. 2002;288:2123-2129.

This paper is the product of a larger, prospective study of the genetic and environmental risk factors for Alzheimer's dementia (AD). Participants are 1357 men and 1889 women recruited from a single county in Utah. Enrollment occurred in 1995-1997, and this report is based on 3 years of follow-up. Determination of AD included the Mini-Mental State examination, the Dementia Questionnaire, and then clinical assessment, if warranted. Neuropsychological tests, a structured interview, examination by a geriatric psychiatrist, laboratory tests, and a panel of experts were involved in making each determination of dementia. Most participants were also screened for the "Alzheimer’s gene," the polymorphic genetic locus for Apolipoprotein E (APOE). Information of Hormone Replacement Therapy (HRT) was collected by interview; use was classified by duration into categories of less than 3 years, 3-10 years, and longer than 10 years. Of note, 72% of those using HRT were taking an unopposed oral estrogen.

Over the 3-year follow-up, 35 men (2.6%) and 88 women (4.7%) developed AD. The development of AD was more common in women than in men, but less common among women with any history of HRT. Further analysis indicated that the risk of AD for men and women is equivalent until about 80 years of age, but the risk is roughly twice as high for women after the age of 80 (the mean ages of the men and women in this study at enrollment were 73.2 and 74.5 years, respectively). Logistic regression, which controlled for education, age, the number of APOE alleles, coexistent medical illness, depression, and medications including multivitamin and calcium use, showed a persistent benefit of HRT, in a dose-dependent manner. Former users (mean age, 74.5 years) of HRT had relative hazards of AD of 0.58 for < 3 years’ use, 0.32 for 3-10 years’ use, and 0.17 for more than 10 years’ use compared with nonusers (though the reduction for those with less than 3 years’ use was not statistically significant). For those currently using HRT (mean age, 71.9), the relative hazards were 2.41 for < 3 years’ use, 2.12 for 3-10 years’ use, and 0.55 for more than 10 years’ use (only those current users with 10 or more years’ use had significant changes). Zandi and colleagues note that there appears to be a "time window" for the protective effect of HRT against AD, and speculate that use of hormones within 10 years of AD onset does not confer benefit.

Comment by Barbara A. Phillips, MD, MSPH

One only has to pick up a woman’s magazine or a lay news publication to grasp the public confusion and interest in the issue of hormone replacement for women. US News and World Report’s cover blares, "Making sense of menopause. New drug options. Tailor-made treatments. Choosing the right therapy.1" Women are increasingly sophisticated and informed as they seek our guidance about what to do when faced with this universal issue for women who survive into their 50s. The landmark study from the Women’s Health Initiative last summer2 resulted in the termination of the estrogen-progestin arm (but not the estrogen-only arm) after only 5.2 years because women who got combined HRT had small but significant increases in coronary heart disease, a nonsignificant trend toward invasive breast cancer, and a significant increase in the global index of a variety of adverse outcomes, including strokes and pulmonary emboli. Why was this not discovered earlier? Women using HRT in the earlier, observational studies were healthier than those not using it. Thus, it is important to note that the current study about AD is prospective, not observational, and its findings are likely to be "real." It is also important to note that these and other authors3 suggest that there is a critical period for HRT use if it is to protect against AD; once the disease has begun (within 10 years of onset), HRT appears to offer little benefit. Timing is everything.

Now our discussions with patients about HRT must take on a "good news, bad news" flavor. Cardiovascular disease, thromboembolic disease, and probably breast cancer are increased among users of combined therapy, but colorectal cancer, osteoporotic fractures, and the risk of dementia are reduced. Patients can choose between risks. To a woman in the throes of hot flashes, however, these abstract risks may not matter much; HRT remains the best treatment for menopausal symptoms.4

Meanwhile, the estrogen-only arm of the WHI continues, and we will continue to learn about the risk/benefit ratio of HRT with estrogen alone.

Dr. Phillips, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington, KY, is Associate Editor of Internal Medicine Alert.


1. US News and World Report. November 18, 2002.

2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy menopausal women: Principal results from the women’s health initiative randomized controlled trial. JAMA. 2002;288:321-333.

3. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease. A critical time. JAMA. 2002; 288:2170-2171.

4. Fitzpatrick LA, Santen RJ. Hot flashes: The old and the new, what is really true? Mayo Clinic Proceedings. 2002;77:1155-1158.

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