UK scientists uncover startling new link between HRT and Alzheimer’s

Women using Hormone Replacement Therapy (HRT) to treat menopause-symptoms could be at greater risk of developing Alzheimer’s, UK scientists claim. 

Previous studies have suggested HRT poses a health risk factor but now Liverpool John Moores University claim to have uncovered a new link between it, Alzheimer’s and a rare gene. 

They claim an ‘apolipoprotein E’ gene variant – instructing our bodies to make a protein to transport cholesterol and other fats in the bloodstream – called APOE e4 is ‘firing’ the progression of Alzheimer’s in women undergoing HRT. 

And they warn it calls into question UK drugs appraiser the National Institute for Health and Care Excellence’s (NICE) support for HRT in managing menopausal symptoms. 

First author Dr Ainara Jauregi-Zinkunegi, post-doctoral researcher in neuroscience at LJMU, explained: “We decided to examine the effects of HRT on cerebrospinal fluid biomarkers linked to Alzheimer’s. 

“What we found is that the disease’s fluid pathology is high when HRT use is paired with presence of a gene variant APOE e4 – but not otherwise.”

Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, told the Daily Express: “We need further, longer term, larger studies with more diverse participants to confirm the results and fully understand this risk and to weigh this against the benefits offered by HRT for some women.” 

HRT replaces the hormones oestrogen or progestogen, or both, when women’s periods stop – normally between the ages of 45 and 55. 

It is administered using gels, creams, pessaries, tablets, patches or sprays and is sometimes prescribed during perimenopause, as the hormones start to fluctuate but before menstruation stops altogether. 

The APOE e4 gene variant is present in approximately 1 in 4 people – with only 2-3 per cent carrying two copies – and has previously been hinted at having a link in the development of dementia.

Inheriting the APOE4 gene however does not necessarily mean a person will definitely develop the disease 

The APOE gene comes in several different forms, or alleles. APOE3 is the most common and not believed to affect Alzheimer’s risk – while the rare APOE2 may even protect people from Alzheimer’s.

The reason APOE4 specifically increases Alzheimer’s risk is not well understood. Recent studies suggest problems with brain cells’ ability to process fats, or lipids, may play a key role in Alzheimer’s and related diseases.

The LJMU team – publishing its findings in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association – studied fluid biomarkers data from 136 women.

The woman have an average age of 66 and had no cognitive problems, and the team compared HRT users with non-users, including whether they carried the APOE e4 variant.

Alzheimer’s Disease (AD) pathology is traditionally characterized by the accumulation of abnormal proteins in the brain. These proteins include beta-amyloid (Aβ) and tau.

In the LJMU study, average levels of that biomarker – phosphorylated tau by amyloid beta-42 – were comparable across HRT users and non-users. 

But shockingly they found women using HRT who had at least one APOE e4 gene had levels of the same biomarker over 60 per cent higher.   

They concluded that elevated levels of these biomarkers are likely to indicate increased Alzheimer’s Disease-related pathology in these women and, thus, a higher risk of developing dementia. 

HRT was not associated to higher biomarkers levels in the absence of APOE e4. 

LJMU say if their findings are proven in further studies then it would suggest that women found to have the APOE e4 gene variant should be cautioned against using HRT.

The university adds: “(The” discovery  a gene could be ‘firing’ the progression of Alzheimer’s in women undergoing HRT further calls into question NICE’s support for HRT in managing menopausal symptoms.

Dr Davide Bruno, a Reader in neuropsychology at LJMU, who led the study, said: “If our results are confirmed (in further studies), they would caution against HRT use in women at elevated risk for Alzheimer’s due to genetic susceptibility.

“People who are already at elevated risk of AD, such as those with the e4 variant of APOE, even if currently asymptomatic, may be more susceptible to possible negative effects of hormone replacement.

“There is still a lot we don’t know but it may be prudent to test women for presence of the APOE e4 variant before HRT administration, at least until more knowledge on this matter is acquired.” 

And he added: “We think this may be a scenario whereby exposure to oestrogen might be beneficial for healthy neurons, but in contrast oestrogen might worsen damage in ‘sick’ neurons.” 

In 2021 a study of nearly 400,000 women, found both new and old HRT drugs reduced the risk of diseases that cause dementia. 

The study found that the effects differed based on many things: dose, type of medication, length of treatment, age, and time from menopause. 

Another study in Denmark, following dementia rates of over 55,000 women showed the opposite, that HRT increases dementia risk. 

Part of the reason of the uncertainty is that many studies only show a connection between dementia and HRT, but they can’t tell us if HRT leads to dementia.

On Friday, NHS England told the Daily Express the licensing and prescribing advice for HRT drugs was a matter for NICE.

NICE, funded by the Department of Health and Social Care, recently updated their guidance to GPs last November on HRT for menopause management, including possible links to dementia.

After a detailed analysis of data on links between HRT and conditions such as heart disease, stroke, some cancers and dementia, NICE concluded HRT does not affect life expectancy.

NICE concluded the risk of dementia was slightly higher if women started taking HRT after the age of 65 but said in younger patients there was no elevated risk of developing dementia.

Dr Marie Anne Ledingham, consultant clinical adviser to NICE, said last November: “The risks are very low in the population, and HRT can provide huge benefits at a very difficult point in many women’s lives.”

The Daily Express contacted NICE on Friday for a response to the new LJMU study’s findings.

A NICE spokesperson told us: “Our recently published guideline on the identification and management of the menopause provides reliable evidenced-based information on the benefits and risks of HRT to aid shared decision making between women and their healthcare professionals when discussing management options.

“Our independent committee advised that although HRT is effective for symptoms, it should not be used for the prevention of dementia.

“When new high-quality evidence is published which could affect our recommendations, NICE will review it and consider whether our guideline needs to be updated.

“Women need to feel confident that when they talk to a GP about their symptoms, they will be offered advice and options that meet their needs and supported to make choices that are right for them.

“In order to help women NICE has published a discussion aid on HRT and the likelihood of some medical conditions, to support GPs in their discussions with patients.”

* The LJMU paper ‘Menopausal hormone therapy is associated with worse levels of Alzheimer’s disease biomarkers in APOE4-carrying women’ has now been published in Alzheimer & Dementia.