The relation between hormone usage and Alzheimer risk has been addressed in a large number of observational studies and in 1 primary prevention trial. This body of clinical research has led to important conclusions regarding hormone therapy and dementia, although some important clinical issues remain unsettled.
Protective associations of hormone therapy are reported from a number of studies. These include the Leisure World retirement community [relative risk estimate (RR), 0.65; 95% confidence interval (CI), 0.49–0.88],23
a community-based cohort in northern Manhattan (RR, 0.5; 95% CI, 0.25–0.9),24
the Baltimore Longitudinal Study of Aging (RR, 0.46; 95% CI, 0.21–1.00),25
the Italian Longitudinal Study on Aging (RR, 0.28; 95% CI, 0.08–0.98),26
the Cache County cohort (RR, 0.59; 95% CI, 0.36–0.96),27
and the Multi-Institutional Research in Alzheimer Genetic Epidemiology study (RR, 0.70; 95% CI, 0.51–0.95).28
No protective association of hormone use was reported from a Seattle area health maintenance organization (RR, 1.1; 95% CI, 0.6–1.8).29
Meta-analyses suggest risk reductions of about a third.30,31
Long-term hormone use in these studies is associated with greater risk reductions than short-term use.23,24,27
The interpretation and clinical relevance of these reported associations is challenged by seemingly discrepant findings from the WHIMS trials.32,33
At the time of enrollment, WHIMS participants were community-dwelling women between the ages of 65 and 79 years. Women were generally healthy, but there is suggestion that these volunteers were somewhat less healthy (eg, higher prevalence of obesity) than women in the general population. One hundred eight women developed dementia during the course of the 2 WHIMS trials during mean follow-up periods of about 5 years. Because the trials were halted prematurely, the number of incident cases of dementia was less than anticipated, and separate outcomes were not reported for Alzheimer disease or other specific dementia types. In the estrogen-progestogen trial, the risk of dementia among women in the active treatment group was twice that of women in the placebo group. In the estrogen-alone trial, the risk was elevated by about 50% in the hormone group (). The increased risk in these populations represents about 2 additional cases of dementia per 1000 women per year of hormone use.
Dementia outcomes in the Women’s Health Initiative Memory Study
Women with lower cognitive scores at the time of enrollment, and older women, were much more likely to develop dementia during the course of the trials. The increase in dementia risk became apparent within a few years after treatment allocation.32,33
Because the pathologic features of Alzheimer disease are presumed to begin a decade or more before overt appearance of dementia, WHIMS investigators speculated that hormonal effects on the cerebral vasculature may have contributed to the relatively quick appearance of dementia among women randomized to active treatment.
Women in the WHIMS trials who had used hormone therapy in the past were significantly less likely to develop Alzheimer disease or another form of dementia than women who had not used hormone therapy; prior use did not modify effects of randomized treatment allocation during the WHIMS trials.32–34
This association with prior use is consistent with findings described above from other observational studies of hormone therapy and Alzheimer disease. In general, women who use hormone therapy are better educated, enjoy better health, and engage in healthier lifestyles than nonusers. Such differences might account for protective associations seen in most observational studies.35
Differential recall of prior hormone usage (recall bias) might also underestimate risks of hormone therapy.
There is a further consideration regarding these studies and the WHIMS clinical trials. WHIMS participants differed from many women in observational studies, particularly including the age at which hormone therapy was initiated and used.35
Hormone therapy is most often prescribed for vasomotor symptoms around the time of menopause, taken for several years, and then discontinued. Thus, most hormone use in observational studies occurred at a relatively young age, close to the time of menopause. In contrast, all hormone use during the WHIMS trials occurred only after age 64, remote from the time of menopause.
It is unknown whether estrogen effects on Alzheimer risk are modified by age of use or by use during a critical window close to the time of menopause.36
A protective association was reported for past, but not current, hormone therapy in the Cache County cohort27
; and the protective association of hormone therapy was significantly modified by age in Multi-Institutional Research in Alzheimer Genetic Epidemiology study, being limited to younger postmenopausal women.28