Study suggests hormone replacement therapy may reduce Alzheimer’s risk

Researchers followed more than 180,000 postmenopausal women in the U.K. in the largest study of its kind to date.

They found that women who had used HRT had a 16% lower risk of developing Alzheimer's disease — the main form of dementia — compared with those who had never used it.

The greatest reduction was seen in women who had undergone surgical menopause with a 26% lower risk of developing any type of dementia, compared with non-users.

Researchers from the University of East Anglia (UEA) and the University of Exeter also found that women who naturally had lower lifetime estrogen exposure, due to starting their periods late or early menopause, seemed to benefit more from HRT — with a 16% lower risk of any type of dementia.

Study leader Anne-Marie Minihane said: "Dementia affects millions of people worldwide, with women making up almost two-thirds of Alzheimer's disease cases, the main form of dementia.

"As populations age, understanding how sex-specific factors influence dementia risk is increasingly important.

"In addition to living longer, the reason behind the higher female prevalence is thought to be related to the effects of menopause on brain metabolism and the impact of the main genetic risk factor APOE4 being greater in women.

"We wanted to better understand how HRT could prevent dementia and to assess if particular groups of women may respond differently."

The research team analyzed health data from the UK Biobank, tracking 183,450 postmenopausal women over an average follow-up period of 13.3 years.

During that time, almost 4,000 cases of dementia were identified.

The study examined whether using HRT for at least one year was associated with the risk of developing dementia, and whether that relationship varied depending on biological and genetic factors.

The researchers also took into account other factors that could influence dementia risk and HRT use — including age, socioeconomic factors, other health issues and medication use.

Minihane, from UEA's Norwich Medical School, said: "We found that women who had used HRT were about 10% less likely to develop dementia, and 16% less like to develop the Alzheimer's disease form of dementia, than women who had never used it.

"But the protective association between HRT and dementia was not the same for all women.

"We found that HRT is especially beneficial for women who have gone through a surgical menopause, for example after having their ovaries removed.

"In this group, those who used HRT were around 26% less likely to develop dementia than women who didn't use it.

"We also found that women whose bodies naturally produced less estrogen over their lives — because they started their periods late or hit menopause early — seemed to get more help from HRT.

"Their risk of dementia was around 16% lower with HRT."

Genetics also played a role, according to the findings published in the journal Alzheimers and Dementia.

The associations between HRT use and dementia were stronger in women who carry the APOE4 gene variant — a known risk factor for Alzheimer's.

Minihane said: "This is really important because APOE4 carriers are typically considered at higher risk and have fewer established prevention options."

The age at which women started hormone therapy also appeared to influence outcomes.

Those who began HRT between the ages of 46 and 56 experienced the greatest reduction in dementia risk.

The researchers say that finding supports the so-called "critical window" hypothesis, which suggests that HRT may be more beneficial when initiated closer to the menopausal transition, rather than later in life.

The study didn't find the same level of benefit when HRT was started outside this age range, reinforcing the importance of timing in hormone-based interventions.

Minihane added: "Our findings contribute to growing evidence that hormone therapy's effects on brain health are complex and influenced by individual biological factors.

"While HRT has long been prescribed primarily to relieve menopausal symptoms such as hot flushes and night sweats, this work suggests it may also play a role in long-term cognitive health for some women."

This research builds on a previous study from UEA, which found that HRT use is associated with better memory, cognition and larger brain volumes in later life among women carrying the APOE4 "dementia gene."

The team says their latest findings provide a foundation for more personalized approaches to HRT prescribing — taking into account menopause type, genetic risk, lifetime hormone exposure and age at initiation.

David Llewellyn, from the University of Exeter Medical School, said: "These findings represent a significant step forward.

"Rather than asking simply whether HRT affects dementia risk, we've been able to identify which women are most likely to benefit, and when.

"That's the foundation on which genuinely personalized approaches to women's brain health can be built."

Amanda Collis, from the Biotechnology and Biological Sciences Research Council (BBSRC) which funded the work, said: "This study provides valuable new insights into how menopause and the timing of hormone replacement therapy may influence dementia risk in women."

She added: "The findings suggest that HRT could have greater protective benefits for some groups, highlighting the potential for more personalized approaches to prevention."