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  • Hormone replacement therapy (HRT) is linked to improved memory, cognition and larger brain volumes in some women who at higher risk of developing Alzheimer’s disease.
  • HRT was most effective when introduced during the perimenopausal stage.
  • One of the reasons why HRT may be effective is due to estrogen’s ability to lower cortisol.
  • High levels of cortisol are associated with increased cognitive impairment and neurodegeneration.

Nearly two-thirds of people in the U.S. with Alzheimer’s disease are women.

Because there’s currently no cure for Alzheimer’s disease, researchers are exploring preventative treatments to help protect as many people as possible.

A recent study published in Alzheimer’s Research & Therapy this month showed promising results.

The research found that hormone replacement therapy (HRT) may help protect against Alzheimer’s disease among at-risk women. 

What the study found

Researchers carried out the study in a group of women in the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Some of these women were carriers of the APOE4 gene, which increases a person’s risk of developing Alzheimer’s disease. Overall, the researchers found that HRT was linked to improved memory, cognition and larger brain volumes in women carrying the APOE4 gene.

The results also showed that HRT had the most positive impact during the perimenopausal stage.

“There is a ‘critical window’ where HRT can be neuroprotective. This critical window is likely to be during the transition to menopause, where gradual estrogen decline increases the brain liability to AD-related pathologies,”  Dr. Rasha Saleh, one of the study authors and a senior research associate at Norwich Medical School, told Healthline.

The main takeaway from the research is the power of preventative treatment and taking a proactive approach to protect yourself, especially if you’re at risk.

“Our observational study highlights the importance of targeted approach in the prevention of Alzheimer’s disease,” said Saleh. “Identifying the at-risk APOE4 women and early HRT introduction can be of benefit to cognition. Confirming our findings in a clinical trial would be the next step forward.”

Why Women Are More at Risk for Developing Alzheimer’s Disease

According to the experts we spoke with, one of the main contributing factors as to why women are more at risk for Alzheimer’s disease is a lack of estrogen later in life.

“The impact of estrogen decline on the brain during menopause is emerging as the main reason for the higher prevalence of Alzheimer’s disease in women,” Saleh stated. “Estrogen receptors are expressed throughout the brain, with estrogen regulating multiple physiological processes including neuroinflammatory status, glucose utilisation, lipid metabolism and others. Therefore, estrogen decline can lead to the acceleration of Alzheimer’s disease-related pathologies.”

There are sex differences in many other risk factors associated with AD.

“Education and depression is different between the sexes,” said Jennifer Bramen, PhD,  a senior research scientist at the Pacific Neuroscience Institute in Santa Monica, CA. “Additionally, reproduction is different. We are still trying to understand the effects of challenges during pregnancy such as gestational diabetes and hypertensive pregnancy disorders on AD risk.”

Menopause is one important difference between men and women and is the focus of this research.  

Women become at greater risk for cognitive impairment and AD during the menopausal transition, where they experience a sudden loss of estrogen and its neuroprotective effects, Dr. Bramen explained.

How HRT Impacts Women Carrying the APOE4 Genotype

HRT helps supplement hormones that are affected during the transition into menopause, including the relief of menopausal symptoms. Interestingly, this new research shows that HRT may also play a role in improving cognitive function.

“Being a woman and carrying the APOE4 gene increases the risk of cognitive decline,” said Saleh. “We found that despite carrying that at-risk gene, women on HRT had higher cognitive scores and larger MRI brain volumes in cognition-related regions, especially if started early-during menopausal transition.”

Study authors said that one of the most important findings from the EPAD cohort is the need to challenge many beliefs surrounding early Alzheimer’s disease and its treatment, particularly when it comes to women’s brain health. An impact on cognitive function and brain changes supports the idea that HRT is beneficial.

“We showed in the EPAD cohort that APOE genotype and the age of HRT initiation can be important modulators of the effect of HRT intervention on cognitive function and cognition-related brain volumes and can explain some of the discrepant outcomes,” Saleh said.

The timing of introducing HRT is crucial to its effectiveness.

The study authors found that the earlier the age of HRT was started, the larger the hippocampus volume.

There are numerous mechanisms by which HRT might protect against AD, especially during early menopause. 

“Estrogen attenuates the negative effects of cortisol,” said Dr. Bramen. “Cortisol spikes are a normal part of menopause, and high levels of cortisol are generally believed to increase cognitive impairment and neurodegeneration.” 

According to the National Institute of Health, approximately one in four individuals carry at least one copy of the APOE4 gene.

It’s possible that there are other such subsets of individuals that would benefit in addition to people with the APOE4 gene, Dr. Bramen added.

But the experts say more study will be needed to confirm HRT can help protect against Alzheimer’s disease and what groups may benefit from the treatment.

The bottom line

According to new research, HRT is associated with improved memory, cognition and larger brain volumes in women who carry the APOE4 gene. Individuals who carry the gene have a high risk of developing Alzheimer’s disease.

Researchers found that HRT was most effective when introduced during the perimenopausal stage.

Women who are APOE4 gene carriers are most responsive to HRT, showing greater cognitive ability compared to APOE4-non-HRT users.

Experts believe that HRT can be beneficial because of estrogen’s effect on cortisol. High cortisol levels are linked to cognitive decline and neurodegeneration.

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