Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women: The Cache County Study

Abstract & Commentary

Synopsis: In a prospective observational study of 1357 men and 1889 women, the incidence of dementia increased in women after age 80 and exceeded the risk among men of similar age with an adjusted hazard ratio of 2.11 (range, 1.22-3.86). Women who had ever used HRT had a reduced risk of alzheimer disease compared to non-HRT users, with an adjusted hazard ratio 0.59 (range, 0.36-0.96).

Source: Zandi PP, et al. JAMA. 2002;288:2123-2129.

Zandi and colleagues conducted a prospective study of incident dementia among 1357 men with a mean age of 73.2 years and 1889 women with a mean age of 74.5 years. All participants resided in a single county in Utah. Participants were first assessed in 1995-1997 and then seen again in 1998-2000. The methods indicate that the study was very carefully conducted. Of the cohort, 35 men and 88 women developed Alzheimer Disease (AD) in the 3-year interval. The incidence of AD increased in women after age 80 and was slightly more than double that in men of similar age. Women who used HRT had a reduced risk of AD (26 cases among 1066 women) compared to those who had never used HRT after menopause (58 cases among 800 women). The adjusted hazard ratio was 0.59 with a confidence interval of 0.36-0.96. The results were not explained by a healthy user effect. Risk of AD varied with duration of HRT use, so that a woman’s sex-specific increase in risk disappeared entirely with more than 10 years of HRT exposure. There was no effect of current HRT use unless duration of treatment exceeded 10 years. In the discussion, Zandi et al emphasize that these results agree with previous studies showing that HRT does not confer neuroprotection when started in the decade before onset of AD. This is partly explained by the long prodromal phase of AD that escapes clinical detection. Among current HRT users, 72% were taking an unopposed oral estrogen preparation. The protective effect of HRT appeared to be strongest in those at highest risk, namely those with 2 e4 alleles at APOE, the polymorphic genetic locus for apolipoprotein E.

Comment by Sarah L. Berga, MD

I was tempted to title this abstract "Why can’t a woman be more like a man?" As Zandi et al note, the hazard for AD is roughly equal in women and men until age 80, but if a woman used HRT for 10 years or more, her risk for AD remained as low as men’s after age 80. This is dramatically illustrated in the report in Figure 2B. Although it seems counterintuitive, the brains of older men are actually exposed to more estrogen than are women’s because testosterone is aromatized in situ in the brain to estradiol and the testes continue to make testosterone throughout a man’s life. As Resnick notes in her accompanying editorial (JAMA. 2002;288:2170-2172), there are many reasons to suspect that estradiol may be neuroprotective. These include animal studies showing enhancement of synaptic plasticity, effects on several neurotransmitter systems, reduction in beta-amyloid formation from its precursor protein, and modulation of regional cerebral glucose metabolism. Further, human neuroimaging studies provide evidence that estrogen influences the pattern of brain activation during memory processing and modulates brain activity in specific brain regions affected in the early stages of AD.

The study results are not so surprising. What makes the study so provocative, however, is its careful prospective design and the suggestion that women must use estrogen for 10 years to achieve full neuroprotection. Those hoping for a clear, unequivocal answer as to how to counsel menopausal women asking about HRT are sure to be disappointed, as these results only fuel the HRT controversy. As I indicated in an earlier editorial in July, I suspect that we will eventually find a way to give HRT so that benefits can be maximized and risks minimized. Resnick states that "these new findings emphasize the need for continued research on the optimal regimen, dose, and timing of hormone therapy." Keep in mind that the cholinergic neurons that subserve memory and cognition have been shown to possess primarily estrogen receptor a in rats. If the same is true in humans, then it will be important to give an estrogen that has high affinity for ER-a.

Dr. Berga is Professor and Director, Division of Reproductive Endocrinology and Infertility, University of Pittsburgh.