Women taking hormone replacement therapy (HRT) to relieve menopausal symptoms may be at greater risk of developing dementia and Alzheimer’s disease, a new study suggests.

The research conducted in Denmark involving more than 60,000 women and published in the latest issue of The British Medical Journal, showed that those using HRT treatments – which include tablets containing oestrogen only, or a combination of oestrogen and progestogen, as well as skin patches, gels and creams – were 24% more likely to develop all-cause dementia and Alzheimer’s in later life.

An increased risk was seen not only in long-term HRT users but also in those taking the treatment short-term around the age of menopause – defined as 55 years or younger, as is currently recommended.

These latest findings appear to contradict other studies – including one conducted by the Mass General Brigham Hospital based in Boston, Massachusetts, published in April this year –  that suggested HRT actually protects against cognitive decline if it’s started near the age of diagnosis.

That study found that women who began HRT treatment five or six years after the start of the menopause had higher levels of two key proteins involved in dementia, tau and beta-amyloid.

The researchers in that study admitted more investigations were needed to determine how the menopause and HRT affect the brain. But their early findings suggested starting HRT as soon as the first menopausal symptoms appear may be better not only for brain health but in helping reduce heart disease and other medical symptoms associated with the change of life. 

A number of experts have adopted a circumspect view on this latest Danish research, especially as the team behind it couldn’t distinguish the reasons HRT was being prescribed in the first place from the early symptoms of dementia.

Many menopausal symptoms, such as brain fog, sleep disturbance, confusion and memory problems, can lead some to fear they are showing the early signs of dementia or Alzheimer’s.

Conversely, for some of the women in the study, the symptoms being treated by HRT may actually have been a sign of early neurological changes that would have developed into dementia.

Dr Sarah-Naomi James, senior research Fellow at the MRC Unit for Lifelong Health and Ageing at University College London, said: “The editorial seems very fair – the study has strengths in utilising nationwide data it has available and their effort to try to differentiate between different types and duration of HRT use is admirable, well-needed and seems fairly robust.

“However, the study has fundamental limitations in its ability to interpret and understand the true underlying causal pathways of the observed association, as both the exposure (why you would be prescribed HRT in the first place, and why you would be prescribed certain types and duration of medication use) and the outcome (dementia diagnosis) have many things in common that influence them, and so this association may be artificial.

“For example, changes in sleep or mood are very common symptoms of menopause and reasons to seek out HRT; meanwhile we are starting to understand that sleep and mood may play an important role in the expression and progression of dementia.

“The best way to understand whether HRT medication itself causes dementia comes from clinical trials, and to date, there is not enough evidence to support a direct link from the medication itself, and this new study alone should not change practice.”

Dr Amanda Heslegrave, senior research fellow at the UK Dementia Research Institute, added: “I don’t believe you can suggest a causal link from this data. It is known that many women who seek HRT at or around menopause do so because of concerns around memory and cognition, potentially confounding data.

“There is research that suggests HRT can be protective with respect to dementia, also other research that the paper cites, that HRT is associated with dementia – this suggests to me that we really don’t know the whole story and targeted research is required.”

One such piece of research showing a link between long-term use of HRT and the development of dementia was the landmark Women’s Health Initiative Memory Study, the largest clinical trial on this topic.

But the effect of short-term use of menopausal hormone therapy around the age of menopause, as is currently recommended, remains to be fully explored. The effect of different treatment regimens on risk of dementia is also uncertain.

To try and fill these knowledge gaps, the researchers in Denmark assessed the association between the use of combined oestrogen and progestin (synthetic progestogen) therapy and the development of dementia according to type of hormone treatment, duration of use, and age at use.

Drawing on national registry data, they identified 5,589 cases of dementia and 55,890 age matched dementia-free controls between 2000 and 2018 from a population of all Danish women aged between 50 and 60 years at the turn of the century with no history of dementia and no underlying reason preventing them from using HRT.

Other relevant factors including education, income, hypertension, diabetes, and thyroid disease were also taken into account.

The average age at diagnosis was 70 years. Before a diagnosis, 1,782 (32%) cases and 16,154 (29%) controls had received oestrogen-progestin therapy from an average age of 53 years. The average duration of use was 3.8 years for cases and 3.6 years for controls.

The results showed that, compared with people who had never used HRT, those who had received oestrogen-progestin therapy had a 24% increased rate of developing all cause dementia and Alzheimer’s disease, even in women who received treatment at the age of 55 years or younger.

The rates were higher with longer use, ranging from 21% for one year or less to 74% for more than 12 years of use.

The increased rate of dementia was similar between continuous (oestrogen and progestin taken daily) and cyclic (daily oestrogen with progestin taken 10-14 days a month) treatment regimens.

Use of progestin and vaginal oestrogen only therapies were not associated with the development of dementia.

The researchers admitted that this is an observational study, so couldn’t establish cause, and that they were not able to isolate vascular dementia from other types of the disease or distinguish between tablets and alternative ways to take hormone therapy, such as patches.

What’s more, they couldn’t rule out the possibility that women using hormone therapy had a predisposition to both menopausal vasomotor symptoms, such as hot flushes and night sweats, and dementia.

However, this was a large study based on high quality treatment data with long follow-up time.

The authors were also able to investigate cyclic and continuous hormone formulations separately, as well as age of starting HRT and the length of treatment, allowing them to analyse an important overlooked aspect of this topic – namely the dementia risk in short-term users of HRT around the age of menopause onset, as recommended in treatment guidelines.

As such, they concluded: “Further studies are warranted to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments.”