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Can hormone-replacement therapy affect Alzheimer’s risk in women?


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Hormones may have an impact on an individual’s risk of developing Alzheimer’s disease. Alba Vitta/Stocksy
  • Worldwide, Alzheimer’s disease affects twice as many women as men, partly because women, on average, live longer, but this cannot fully explain the difference.
  • At menopause, estrogen levels drop, and this reduction in hormones may increase the risk of developing Alzheimer’s.
  • Studies into the effect of hormone-replacement therapy (HRT) on Alzheimer’s risk have produced conflicting results, with some showing an increase and others a decrease.
  • A new study has suggested that HRT may decrease the risk of Alzheimer’s in women who have a gene that increases their risk of the condition.

The World Health Organization predicts that by 2050 some 139 million people worldwide will be living with dementia. According to the CDC, the most common form of dementia— Alzheimer’s disease (AD)—accounts for up to 80% of dementia cases, so by 2050, it is likely that, globally, more than 100 million people will have AD.

AD is largely a disease of old age, so these increases are mostly due to the aging population. And living longer is one reason why women are almost twice as likely as men to develop AD.

“It remains unclear in 2023 why more women develop Alzheimer’s dementia than men. It is true, that on average, women live longer than men. It is also true, that on average, male brains tend to have higher total brain volumes and are bigger than female brains.”

Dr. Clifford Segil, D.O., neurologist at Providence Saint John’s Health Center in Santa Monica, California, speaking to Medical News Today

As age alone cannot explain the higher prevalence in women, experts are investigating other possible causes. One hypothesis is that the drop in hormones, particularly estrogen, at menopause, may increase dementia risk.”

Some previous research found that HRT reduced the risk of all neurodegenerative diseases, including Alzheimer’s disease, particularly when used long-term.

Now, researchers from the Universities of East Anglia and Edinburgh, in the United Kingdom, have found that HRT may be particularly beneficial in women with a genetic risk factor for AD.

Around menopause, many women opt for HRT to alleviate symptoms such as hot flashes, night sweats, anxiety, and reduced sex drive.

Dr. Jennifer Bramen, senior research scientist at the Pacific Neuroscience Institute in Santa Monica, California, suggested one way HRT might work in decreasing Alzheimer’s risk.

“There are numerous mechanisms by which HRT might protect against AD, especially during early menopause. For example, estrogen attenuates the negative effects of cortisol. Cortisol spikes are a normal part of menopause, and high levels of cortisol are generally believed to increase cognitive impairment and neurodegeneration,” she explained to MNT.

In this new study, published in Alzheimer’s Research and Therapy, the researchers analyzed data from 1,178 women aged over 50 years who were taking part in the European Prevention of Alzheimer’s Dementia (EPAD) initiative. The women did have any form of dementia at baseline.

The researchers were particularly interested in whether HRT had more impact on women with the APOE4 gene. Having a single copy of APOE4 approximately triples a person’s risk of developing AD; having two copies can increase that risk by 8-12 times.

The gene is carried by around 25% of people, with 2-3% of people having 2 copies of the gene. To compare the effect of HRT on AD risk in those with and without the gene, the researchers divided the participants into those with APOE4 and those without.

Anyone who was being, or had been, treated with oral or transdermal estrogen, or estrogen plus progestogen, was recorded as having HRT.

All the participants undertook a range of cognitive tests to assess skills, including attention, delayed memory, immediate memory, language, and visuospatial construction. They also underwent MRI scans to assess brain volume, which decreases with AD.

For women without the APOE4 gene, HRT made no difference to cognitive function or brain volume.

In women with the APOE4 gene, HRT was associated with better memory and larger brain volume, with the greatest effect seen in those who started HRT earlier.

In people with AD, the hippocampus — a part of the brain that has a major role in learning and memory — shrinks by up to 25%. For the APOE4 carriers in this study, early HRT was associated with a greater hippocampal volume, which may indicate that HRT had a protective effect.

“The study throws out the idea that early treatment with HRT during a critical window may be neuroprotective, and claims like this arise often in research papers but are extremely hard to prove in clinical practice. One proposed mechanism would be HRT slows down brain shriveling or atrophy in women with APOE4 per the results of this paper.”
— Dr. Clifford Segil, speaking to MNT

So, for women with a genetic predisposition to develop AD, starting HRT as soon as menopausal, or even perimenopausal, symptoms are noticed may be beneficial.

Prof. Michael Hornberger, professor of applied dementia research at the University of East Anglia’s Norwich Medical School, one of the study authors, commented:

“It’s too early to say for sure that HRT reduces dementia risk in women, but our results highlight the potential importance of HRT and personalized medicine in reducing Alzheimer’s risk.”

He added that the next stage of research needed was an intervention trial to confirm the impact of early HRT on cognition and brain health. This should be followed by an analysis of which types of HRT are most beneficial.

Dr. Emer MacSweeney, CEO and consultant neuroradiologist at Re:Cognition Health welcomed the study, and emphasized the need for further research.

“Circa 25% of the population carry an APOE4 gene and women develop Alzheimer’s disease more frequently than men. Any correlation of this type, that could lead to an intervention to decrease the risk of developing Alzheimer’s, is desperately needed, to reduce lifetime risk of Alzheimer’s,” she said.

“Further prospective research, in a larger study, will hopefully support and confirm the benefit of HRT, and identify exactly which HRT is most beneficial,” she added.



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