Long-term HRT Tied to Greater Risk for Alzheimer Disease

Marlene Busko

March 07, 2019

Postmenopausal women who received hormone replacement therapy (HRT) had a "small absolute increased risk" of developing Alzheimer disease in a nationwide case-control study from Finland.

"The present study indicates that the use of systemic hormone therapy, once claimed to be protective against Alzheimer's disease, is accompanied with a 9–17% increase in the risk of the disease in postmenopausal women, whereas the exclusive use of vaginal estradiol shows no risk," the researchers report in an article published online March 6 in the BMJ.

"Even though the absolute risk increase for Alzheimer's disease is small, our data should be implemented into information for present and future users of hormone therapy," Hanna Savolainen-Peltonen, MD, PhD, Department of Obstetrics and Gynecology, University of Helsinki, Finland, and colleagues conclude.

The findings showed that "particularly long-term exposure to hormone therapy is associated with an increased risk of Alzheimer's disease," they add. The increase in risk "is not dependent" on the age at which treatment starts.

Thus, the "evidence is reassuring for women needing a few years' treatment for menopausal symptoms," Pauline M. Maki, PhD, Departments of Psychiatry, Psychology, and Obstetrics and Gynecology, University of Illinois at Chicago, and colleagues observe in an editorial that accompanies the article.

"For women in early menopause with bothersome vasomotor symptoms, no compelling evidence exists of cognitive concern from randomized trials" of HRT, according to the editorialists, "and instead there is reassurance about cognitive safety."

On the other hand, they too stress that "concerns about longer term use of estrogen plus progestin on cognitive outcomes remain."

Does HRT Prevent or Promote Alzheimer Disease?

Observational studies have reported that HRT is associated with a reduced risk for Alzheimer disease, the authors note, but the studies lacked a placebo group, and the women who received HRT may have been healthier to start with.

This criticism "gained strong support" when the placebo-controlled Women's Health Initiative Memory Study (WHIMS) reported that postmenopausal women who took estrogen had an increased risk for impaired cognition and probable dementia.

However, WHIMS was criticized because the women started taking HRT at age 65, long after menopause started and later than usual in clinical practice.

To investigate this issue further, the researchers conducted a case-control analysis, using data from national registries in Finland.

They identified 84,739 postmenopausal women who received a diagnosis of Alzheimer disease from a neurologist or geriatrician between 1999 and 2013.

The investigators matched these women with 84,739 women who were the same age and lived in the same area (hospital district) but who did not develop Alzheimer disease.

Alzheimer disease was mostly diagnosed when the women were aged 80 years or older (56%) or 70 to 79 years (37%), and rarely when they were younger than this (7%).

Of the women with Alzheimer disease, 69% had not used HRT, 13% had used vaginal estradiol, and 1% had used tibolone (multiple brands).

The remainder had used systemic HRT — more often, estrogen/progestin therapy (63%). The remainder took estradiol only.

Of the patients who took systemic estradiol, 90% used an oral formulation; the remaining 10% used transdermal formulations (either patches or gels).

Overall, women who received systemic HRT that only contained estradiol had a 9% increased risk of developing Alzheimer disease (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.05 – 1.14).

Women who received systemic HRT consisting of estrogen plus progestin had a 17% increased risk (OR, 1.17; 95% CI, 1.13 – 1.21) of developing this disease. The risk was similar for different progestins.

The researchers estimate that nine to 18 excess cases of Alzheimer disease per year would be diagnosed in 10,000 women aged 70 to 80 years who used HRT, especially if they used it for more than 10 years.

Large Sample Size, but Limitations to Registry Studies Remain

The researchers say this is one of the largest studies of the association between HRT and Alzheimer disease; it used data from a reliable registry, and the patients' diagnoses were confirmed.

The editorialists agree: "There are many advantages to examining hormone use and Alzheimer's disease in Finland," including the large sample size of almost 85,000 women, the availability of national drug registries that document hormone therapy prescriptions and purchases, long follow-up, and well-validated dementia diagnoses.

These strengths, however, "are countered by the substantial limitations common to all registry studies," they point out. These include the lack of information on potential confounding factors, such as hysterectomy/oophorectomy, cardiovascular risk factors, diabetes, apolipoprotein E4 genotype, and other risk factors for dementia.

In addition, because it is an epidemiologic observational study, cause and effect cannot be determined, the researchers acknowledge.

The study was supported by a Helsinki University Hospital research grant and the Jane and Aatos Erkko Foundation. Savolainen-Peltonen has received speaker and consulting fees from Mylan and funding for congress trips from Merck Sharp & Dohme. Disclosures of the other authors' relevant financial relationships are listed in the original article. Maki has received honorarium from Mylan for talks that were unrelated to the current topic. The other editorialists have disclosed no relevant financial relationships.

BMJ. Published online March 6, 2019. Full text, Editorial

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