One of the biggest claims about Menopause Hormone Therapy (MHT) is that it should be taken prophylactically to prevent dementia and Alzheimer’s Disease later in life, even in those women without menopause symptoms. 

The logic is that an oestrogen starved brain is a fertile ground for cognitive decline, increased inflammation in the brain and progression to disease.

Yet no guidelines anywhere in the world recommend asymptomatic women using MHT to prevent dementia. Why?

Oestrogen and the brain

Oestrogen receptors are found in many parts of the brain including those that impact learning, memory and cognitive functions such as planning, organising and decision-making. Extensive research in animals has shown that oestrogen is neuroprotective, and studies in women who’ve had induced menopause well before the average age of menopause (around 51) have found increased risk of dementia and cognitive impairment. These risks seem to be reduced in those taking oestrogen, leading to speculation that MHT could protect cognitive health in all women – as neuropsychology  experts from Monash University and Royal Melbourne Hospital sum up here.  

But how solid is the research?

University of Chicago’s Professor Pauline Maki, who was integral in discovering where the oestrogen receptors are in the brain and how hormones altered them, was looking at the role of MHT in brain fog more than two decades ago—and initially she was  optimistic that this would be the answer..

“I was a ‘believer’. I thought, ‘universally, it looks as though the loss of oestrogen alters memory, it alters brain function and the like’. But then the randomized trial data came out, and it wasn’t just one study, it wasn’t just two studies, it was four large scale randomized trials that showed that in women without significant hot flashes, hormone therapy had no effect on them. None. Zero. Zip. So, I had to accept those data and say, ‘You know what? I was wrong.’ I based it on the observational data. I thought it would have an effect, and it didn’t,” she told the Menopause Research and Education fund.

Maki, who is a professor of Psychiatry, Psychology and Obstetrics & Gynecology, says the much-cited benefits have been cherry-picked and the majority of observational studies show there may be a risk rather than benefit, or at best a neutral outcome. 

“It’s exactly, and I mean exactly, the opposite” of what she’d expected. “The four most recent large scale studies have actually shown a significant increased risk of Alzheimer’s disease in women who’ve used hormone therapy. And it doesn’t matter what the formulation is, it doesn’t matter what the route of administration is, it doesn’t matter what oestrogen or progesterone you choose, the signal is there.” 

These studies include a 2019 study from Finland, a 2021 study from the UK, a 2023 study from Taiwan, and another 2023 study from Denmark. 

Findings ranged from 17% to 24% increased risk for those taking combined MHT, with factors such as the duration and age that women started the treatment playing a role. (There was also a neutral to small negative effect on Alzheimer’s/dementia risk for those taking oestrogen-only therapy in the UK and Finnish studies respectively).

Conflicting results

However, those arguing in favour of MHT for dementia prevention note limitations within the studies finding increased risk—such as not accounting for severe or poorly controlled vasomotor symptoms which may have been more common in those who developed dementia.

The type of MHT in the studies also varies— or is no longer commonly used in western countries. The Women’s Health Initiative showed that conjugated equine oestrogen (CEE) and hydroxy progesterone acetate doubled the risk of all cause dementia in women over age 65, but CEE alone had beneficial effects. 

But another study showed something different. A study of 27,000 women showed a 26% reduced risk of Alzheimer’s disease in the women who take the oestrogen alone. Professor Maki says the finding was “exciting news. Something prevented dementia.”

Unfortunately, the number needed to treat was enormous, Professor Maki says.

“You need to treat 2004 women to prevent one case of dementia … that means 2003 women took it without getting any benefit, but potentially accumulating those rare harms” of breast cancer.

Making sense of the conflicting results

A 2023 analysis of 51 studies looked at all the conflicting results and noted that older forms of MHT were used or the cohorts were often older when they started treatment. It incorporated results from other observational studies, including one which showed a protective effect for AD and all-cause dementia as well as other neurodegenerative diseases like Parkinson’s Disease, MS and amyotropic lateral sclerosis. But these types of studies have drawn criticism too, as they do not show causality and the populations in them are more likely to be white, well-educated and better off.

The authors concluded that the mostly observational data showed there was a ‘window of opportunity’, as there is with the heart, for initiating oestrogen therapy.  If started around the menopause transition it ‘may support neurological function and reduce the risk of future AD among eligible women.”

But Professor Maki disputes that menopause itself is a risk factor. 

“Let’s look at a group of 70 year old women. What percentage of them have been through this loss of oestrogen? 100%.  And what proportion of those women will get demented? About 20%. What proportion of men will? About 19% So really, is there this cause effect issue with the loss of oestrogen and Alzheimer’s disease? It can’t be that simple. The data just don’t bear it out.”

Until around the age of 80 the rates of dementia and AD are pretty equal in both men and women. It’s not until the 80s that women start to outstrip men in incidence, an evaluation of the data shows.

The next question is, who then are the vulnerable women? 

“In my mind, it’s the many, many, many women who’ve gone untreated for the menopause symptoms. I still adhere to the belief that we must increase the uptake of hormone therapy for symptomatic women, absolutely, 100% agree with that, because I think it does protect their brain” in that group of women, Professor Maki says. 

 “We do know that at minimum, women who have persistent hot flashes are at increased risk for cardiovascular events, cardiovascular disease and cognitive decline, right? What we don’t know is whether or not that’s causal, because you can imagine that the same third factor, say, a poor vasculature, could cause both worse hot flashes and a later risk of heart disease,” she says. 

Impact of vasomotor symptoms

“We do have a proof of concept that if you treat the hot flashes, memory improves. Because we did a randomised trial of a non-hormonal intervention called stellate ganglion blockade. And the reason I used it is because it’s not known to improve cognition generally, but it treats hot flashes. And we asked the question, if you took away the hot flashes does memory get better? And the good news is, it did show some evidence of cause and effect.”

Vasomotor symptoms at night may be the worst because they disrupt sleep – and many women may not even know they’re having them. During one of her trials, she wore a sensor at night and was surprised to find she had three hot flushes that she had no idea about.

Professor Maki says brain scans of people with vasomotor symptoms resemble those with sleep apnoea and suggests those changes may be a marker of women at risk of Alzheimer’s. 

She and her colleagues have shown that there are “associations between stroke-like lesions in the brain called white matter hyperintensities and hot flashes, and that’s exactly what you see with sleep apnoea, and it’s exactly what you see with hypertension. And so, you take these multiple risk factors, let’s say I have a little hypertension, I have a little sleep apnoea, and I have my hot flashes, and then suddenly my female brain is very vulnerable.”

She says that “women do feel better on hormone therapy, and I think their cognition may very well feel better, but it’s probably because they’re having fewer hot flashes, they’re sleeping better, and maybe their moods a little bit better because of all that.” 

But if they aren’t having vasomotor symptoms “there’s zero evidence to suggest it’s beneficial” for preventing Alzheimer’s disease or other forms of dementia.

Genetic risk factors

People with the APOE e4 gene are at increased risk of older-onset Alzheimer’s disease, and there’s evidence that women with this genetic risk can benefit from taking MHT. 

The Mirage Study  showed a potential benefit for  those who took MHT between the ages of 50-63. 

Lifestyle factors are crucial for brain health

It’s too early to say if MHT will prevent dementia. Overall though Professor Maki says the research highlights the need for treating vasomotor symptoms, but simply taking a pill isn’t enough. Diet, exercise, not smoking and reducing alcohol consumption are vital to brain health. The Lancet Commission’s 2024 report has listed 14 modifiable risk factors, including two new ones (untreated vision loss and high LDL cholesterol).

“I’d hate to see women not engaging in the things that we do know improve our brain health and make our brains more resilient to Alzheimer’s disease, and instead, to take a pill that you know at best is neutral if they don’t have symptoms,” Professor Maki says.

“So, we need to be prescribing and engaging in the activities that really work. I fear that women will check the box mentally and say, ‘Oh, I’m on hormones. I’ve already done the hard work for dementia’” instead of doing what we know can make a difference.”

Fiona Clark is the author of the forthcoming book Menowars, a socio-political look at menopause and women’s health.