By Jeffrey T. Jensen, MD, MPH, Editor
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports that he is a consultant for and receives grant/research support from Bayer, Abbvie, ContraMed, and Merck; receives grant/research support from Medicines 360, Agile, and Teva; and is a consultant for MicroChips and Evofem.
SYNOPSIS: A 20-year prospective cohort study from Finland did not provide strong evidence that hormone replacement therapy prevents dementia except among women who self-reported long-term use.
SOURCE: Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology 2017; Feb 15.: doi: 10.1212/wnl.0000000000003696 [Epub ahead of print].
Several case-control and other epidemiologic observational studies support a decrease in the risk of dementia associated with use of postmenopausal hormone replacement therapy (HRT). Imtiaz et al used the Kuopio Osteoporosis Risk Factor and Prevention cohort to study the relationship between HRT use and the subsequent development of Alzheimer’s dementia (AD). This population-based cohort included all women between 47-56 years of age who were residents of Kuopio Province, Eastern Finland, in February 1989. Out of a total population of 14,220 women in the area, 13,100 (92.1%) responded to a baseline survey and completed a health questionnaire that covered demographics; lifestyle; medical, surgical, and reproductive history; medications, including type and duration of HRT use; and other personal characteristics such as age, height, weight, smoking, alcohol consumption, occupation, and physical activity. Women who responded to the baseline questionnaire received follow-up queries every five years. The most recent sample from 2009 included responses from 8,195 women (62.6% of the original cohort). The primary outcome variable was clinically verified AD diagnosis. To assess this outcome, the authors used the Finnish Social Insurance Institution (SII) special reimbursement register that contains information on drugs used for chronic illnesses such as AD. This database likely captures most cases of AD, as Finnish Current Care Guidelines recommend that all persons with AD receive antidementia drugs (unless there is a specific contraindication). However, to receive reimbursement for drug costs, a medical statement of a clinically verified AD diagnosis must be submitted to SII. Systemic HRT use was assessed at each questionnaire by self-report, with number of years of use calculated. The authors also made use of the national prescription drug registry to verify HRT use.
Overall, women who developed AD during the 20-year follow-up interval were older and more likely to be menopausal at baseline. The average age at AD diagnosis was 72.3 years. While any history of HRT use did not change the risk of AD, a trend toward protection emerged with longer duration of self-reported use, with an approximately 50% reduction in risk seen in women reporting more than 10 years of HRT (adjusted hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.31-0.91).
COMMENTARY
Does this observational study support or refute the hypothesis that HRT can reduce the risk of AD? The authors provided a cautious interpretation of their own data, concluding that “Our results do not provide strong evidence for a protective association between postmenopausal HRT use and AD or dementia, although we observed a reduced AD risk among those with long-term self-reported HT.”
Although at first glance this looks like a negative study, on closer review, the data confirm the results of earlier research. The best data we have evaluating the long-term effects of HRT on AD come from the Cache County Cohort, a prospective study of incident dementia in men and women residing in a single county in Utah.1 The Utah study enrolled an older group of subjects (men and postmenopausal women in their 70s) than the Kuopio cohort (perimenopause to early menopause). Both studies assessed HRT use and tracked incident diagnosis of AD. In the Cache County study, men and women were equally likely to develop AD up to about the age of 80, when the relative risk for women more than doubled. However, Utah women who reported any use of HRT had a reduced risk of AD compared with non-HRT users (adjusted HR, 0.59; 95% CI, 0.36-0.96), and the reduction in risk showed a strong linear relationship with duration of use becoming significant only among women using HRT for more than 10 years.
The absence of an overall effect of HRT on AD in the Kuopio Cohort could be due to the younger age of the Finnish women, who would have ranged from age 68-76 years at the time of the 2009 survey. That is roughly the age at which women in the Cache County cohort began participation. Still, the magnitude of the protective effect of long-term (> 10-year) HRT on AD risk seen with both studies is remarkably consistent.
We recently reviewed data from the Elite-Cog2 and KEEPS-Cog3 studies. Both explored the hypothesis of a critical window for initiation of HRT and found no treatment-related benefit of HRT with respect to cognitive function. Although the outcomes of these studies do not support use of estrogen therapy to prevent subtle cognitive decline in postmenopausal women, this does not rule out a potential protective effect on the subsequent development of AD. The consistent finding so far from the Cache County and Kuopio cohorts is that duration of treatment matters, with at least 10 years of use an important goal of therapy. In both studies, current use of shorter duration did not reduce risk.
As we evaluate these results, we must consider the strengths and weaknesses inherent in study design. Both studies used a prospective cohort scheme that allowed incident diagnoses of AD, with the diagnosis validated using medical records. However, a healthy user effect could confound the results. The magnitude of the effect, about a 50% reduction in risk, approaches the threshold for resolution of this study design (two-fold difference) for consideration of clinical importance. Although cognitive benefits are not an indication for HT, healthy postmenopausal women should consider these results as they debate duration of treatment. Often, the timing of HRT discontinuation becomes an arbitrary decision when a woman no longer experiences bothersome symptoms. Women who tolerate therapy well may wish to continue treatment for at least 10 years to maximize protection against the development of AD.
REFERENCES
- Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: The Cache County study. JAMA 2002;288:2123-2129.
- Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology 2016;87:699-708.
- Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: Findings from the randomized, controlled KEEPS-Cognitive and Affective study. PLoS Med 2015;12:e1001833.
A 20-year prospective cohort study from Finland did not provide strong evidence that hormone replacement therapy prevents dementia except among women who self-reported long-term use.
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