Hormone replacement therapy tied to Alzheimer’s risk, study says

An observational study on hormone replacement therapy in nearly 85,000 postmenopausal Finnish women found that those on such therapy had a very small increased risk for Alzheimer's, especially when using combination hormones long-term.

HELSINKI — An observational study on hormone replacement therapy in nearly 85,000 postmenopausal Finnish women found that those on such therapy had a very small increased risk for Alzheimer’s, especially when using combination hormones long-term.

The study, published Tuesday in the BMJ, found an additional 9 to 18 per 10,000 women using hormone replacement could be diagnosed each year with Alzheimer’s beyond the number expected to develop the disease. The association was highest for women who used hormones for 10 years or more and those who used an oral combination of estrogen-progestogen rather than estrogen alone.

But the study’s authors say the results cannot show a cause-and-effect relationship between the use of hormones and an increased risk of Alzheimer’s. That’s partly because the study was not able to capture age and other risk factors for comparison, such as genetic risk for Alzheimer’s, diabetes and cardiovascular disease.

“While this large study suggests that women who received some forms of hormone therapy were slightly more likely to be diagnosed with Alzheimer’s, it doesn’t show that hormone therapy is responsible for this increased risk,” said David Reynolds, chief scientific officer of Alzheimer’s Research UK, in a statement. Reynolds was not involved in the study.

“Studies that look for patterns in medical records can be extremely useful for identifying factors linked with Alzheimer’s risk, but they can’t tell us the root cause of that link,” he said.

Some experts say that younger women facing menopause should not use the findings to make any decisions or changes in their use of hormone replacement therapy, often called HRT.

“This increase was so small, it shouldn’t cause alarm or deter women from their prescribed treatment — particularly those taking it over a short period of time,” James Pickett, who heads research at the Alzheimer’s Society in London and who was not involved in the new research, said in a statement.

“Even if HRT increased the future risk of Alzheimer’s, several years of treatment would be needed, and the effect is marginal,” said Channa Jayasena, a clinical senior lecturer at the Imperial College of London, who was also not involved in the study.

“The results of this study should not change the way HRT is prescribed or viewed,” he said in a statement.

A woman’s disease

Alzheimer’s is a progressive mental deterioration of the brain that destroys memory and thinking skills until the person is unable to do even the simplest of tasks. The disease is thought to be caused by a buildup in the brain of beta amyloid plaques and protein tangles called tau.

Alzheimer’s predominately attacks women. In the United States, almost two-thirds of the nearly 6 million American’s living with Alzheimer’s are female, according to the Alzheimer’s Association. Of the 850,000 people living with dementia in the UK, 500,000 are women.

Women live longer than men, and because older age is the highest risk factor for dementia, a longer life can explain a good bit of the discrepancy. But the role of estrogen in women’s lives — and the lack of it after menopause — may also play a factor by leading to deficits in brain metabolism.

For most women, hormone replacement therapy comes into play at early menopause, typically between 50 and 55, when hot flashes, night sweats, insomnia, mood changes and mental fog appear due to the disappearance of sex hormones called estrogen and progesterone.

The type of HRT used depends on whether a woman has a uterus: Women who don’t must use estrogen-only HRT; those with a uterus must use a combination of estrogen and progesterone to avoid thickening of the lining of the womb. Recently, replacements for progesterone have broadened choices for women.

A hot mess of studies

How does the use or non-use of hormone replacement therapy affect the risk of dementia and Alzheimer’s? Numerous studies, including this new research, have presented a stew of conflicting results.

“I am surprised by the results of this study, since other studies have found that HRT actually improves cognitive function,” Jayasena said.

A 1998 meta-analysis of available research found a 29% reduction in Alzheimer’s disease risk for women using hormone replacement. In fact, three “high quality, randomized trials” have provided reassurance that hormone therapy does not “adversely influence cognition in young, postmenopausal women,” University of Illinois psychology professor Pauline Maki wrote in an editorial accompanying the new Finnish study.

But the only randomized trial on the topic — using data from the Women’s Health Initiative Study, a long-term United States study designed to look at ways to prevent heart disease, osteoporosis and breast and colon cancer in women — dealt a severe blow to that positive trend.

Early results, published in 2002, found that the estrogen-progestogen combo of HRT increased the risk of heart disease as well as stroke, blood clots, dementia and breast cancer. The study was halted early due to the dangers.

By the end of the year, hormone therapy use dropped 30% when analyzed by insurance claims. By 2009 hormone therapy claims had dropped more than 70%.

Then,10 years later, the Women’s Health Initiative reversed its findings. Because the original analysis looked at women 65 and older, who were already at greater risk for heart attacks, blood clots and stroke, the initial results were flawed because they failed to consider a woman’s age at the start of replacement therapy.

The conflicting research led to a prevailing theory among scientists: the “timing hypothesis.” The timing of the delivery of hormones is key, this theory said, with cognitive benefits seen for women using HRT in early menopause but not for those who begin the treatment at 65 and older, when it might even be harmful.

What’s needed to resolve the ongoing debate, University of Wisconsin clinical psychologist Carey Gleason said, is the gold standard: a randomized, placebo-controlled study.

Gleason points to a long-term research project called the Keeps Continuation Study, which she says will examine “cognition, mood and amyloid deposition more than a decade after women were randomized to one of two forms of HRT or a placebo. The findings will provide better insights than purely observational data.”

Data collection on the KEEPS study is just starting, Gleason said, with results at least four years away.

Stay the course for now

Where does the new study leave us? It had some advantages, Maki said, including a very large population of women, validated Alzheimer’s diagnoses and the ability to document use of the hormones via a national drug registry.

But she and other reviewers suggest that the study does little to change thinking about the short-term use of HRT in younger women.

“Correlation cannot infer causation,” Maki wrote. “Considering the totality of the evidence, these findings should not influence clinical decision making about the use of hormone therapy for symptom management.”

Reynolds, of Alzheimer’s Research UK, agreed. “Hormone therapy provides important benefits to many women, helping to combat the symptoms that menopause can bring,” he said. “Women who require hormone therapy should not be put off by these results, and anyone concerned about the effects of this treatment should speak to their doctor.”

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