Long-Term HRT Use May be Associated with an Increased Risk of Alzheimer Disease

There has been mixed evidence regarding whether there is an association between hormone replacement therapy (HRT) and Alzheimer disease. Some observational studies support the protective effect of hormone therapy on Alzheimer disease.

A 2003 randomized controlled trial, the Women’s Health Initiative Memory Study (WHIMS), evaluated the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo.¹ This study found that there was an increased risk of dementia in postmenopausal women aged 65 years and older who received estrogen plus progestin medications.¹ However, hormone therapy was started in women aged 65 years and older in this study, which is generally older than normally initiated in clinical practice to treat menopausal symptoms.

The most recent observational study compared the use of hormone therapy between Finnish postmenopausal women with and without a diagnosis of Alzheimer’s disease.² Data on hormone therapy was utilized from the Finnish national drug reimbursement register. Almost 85,000 postmenopausal women who were diagnosed with Alzheimer disease in Finland from 1999 to 2013 were evaluated.² About 75% of the study participants had been taking hormone therapy for more than 10 years, and these women started treatment before age 60 years.²

The study concluded that use of systemic hormone therapy was associated with a 9-17% increased risk of Alzheimer disease.² There was no difference in the risk between estrogen only and estrogen and progestin combination products. However, the use of vaginal estrogen did not increase the risk of Alzheimer disease.²

It is important to keep in mind that since this is an observational study, it can only show associations and not a cause-and-effect relationship. Also, there was no baseline demographic data for known risk factors for Alzheimer disease included in the study.²

Pharmacists should educate patients that the risk of developing Alzheimer disease is small, and short term use should not pose a problem. Individuals should try to avoid long-term use of hormone therapy that is greater than 10 years.

There is currently ongoing research known as the Kronos Early Estrogen Prevention Study (KEEPS) Continuation that is evaluating the effects of hormone therapy and normal aging on cognitive performance, imaging markers of Alzheimer disease, and brain structure in women who participated in the original KEEPS trial.³ This is a follow-up study evaluating these women 13 years after enrollment.

Additionally, the study participants were randomized to receive oral or transdermal estrogen treatments or placebo within 3 years of menopause.³ Since this study is more robust, it may shed light on the link between Alzheimer disease and hormone therapy.

References

• Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;28:289(20):2651-2662.
• Savolainen-Peltonen H, Rahkola-Soisalo P, Vattulainen P, et al. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study. BMJ. 2019; 364:l665. doi: 10.1136/bmj.l665.
• The Kronos Early Estrogen Prevention Study (KEEPS) (KEEPS). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03718494. Last updated February 6, 2019. Accessed March 9, 2019.