Studies have shown that women are at increased risk of Alzheimer's disease after 80 years of age. There have been mixed results from studies of the effect of hormone replacement therapy (HRT) in preventing or delaying the onset of Alzheimer's disease in older women. Zandi and associates studied this relationship to see if the risk-reducing effects of HRT varied in relation to the duration and frequency of exposure.

In a longitudinal study called the Cache County study, 5,092 participants (2,928 women), 90 percent of whom were at least 65 years of age, were screened for dementia between 1995 and 1997. Between 1998 and 2000, a second assessment for new cases of dementia was made among the 4,119 surviving participants (2,401 women), and they were followed until the year 2000. Participants with a positive screening test underwent a thorough clinical evaluation for dementia. A total of 185 cases of incident dementia were identified in the first stage of the study. Initial interviews with all female participants assessed previous HRT use and duration of HRT use. The authors compared characteristics of HRT users and nonusers and the risk of Alzheimer's disease among HRT users, nonusers, and men.

After exclusions, 1,066 women (56.4 percent) reported HRT use at any time, with mean exposure duration of 11.6 years. The study results confirmed previous findings that Alzheimer's disease was significantly more common in women than in men after 80 years of age. Alzheimer's disease was less common among women with a history of HRT use, and a longer duration of exposure was associated with greater risk reduction. However, compared with nonusers, only former users showed significantly reduced risk. Former users who had used HRT for more than 10 years had an estimated fivefold lower risk of Alzheimer's disease. In current users, only patients who had been receiving HRT for more than 10 years showed any risk benefit.

The authors conclude that HRT, when used for at least 10 years, lowers the risk of Alzheimer's disease in women to the same risk level as that in men. The authors speculate that the greatest protective benefit may occur if HRT is initiated at menopause, when the precipitous decline of endogenous estrogen may have a particularly damaging effect on neurons.

editor's note: This is a well-designed study that addresses healthy-user bias by including questions about calcium and vitamin use. These were not associated with Alzheimer's disease risk reduction, minimizing the likelihood that the study findings were biased toward a category of patients who were at low risk for Alzheimer's disease because of healthy lifestyle factors that weren't accounted for in the study.—c.w.