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鈥淲E ALL expect the hot flashes,鈥� says Lynne Wardale, who started experiencing the symptoms of the menopause around 15 years ago, when she was 48. 鈥淚 would get them daily, and sometimes they would go on for half an hour. But I wasn鈥檛 expecting the migraines or the mood swings.鈥�

Her sister, Vicki Henderson, experienced intense anxiety when she went through it in her early 40s. 鈥淚 was short-tempered and experienced a bit of forgetfulness, as well as insomnia,鈥� she says.

The menopause directly affects half of us, yet there鈥檚 a lot we still don鈥檛 understand about it 鈥� not least why it impacts on mood, memory and concentration. But, surprisingly, these cognitive effects may hold the key not only to safely treating this change itself, but also to tackling a disease that presents similar symptoms 鈥� 础濒锄丑别颈尘别谤鈥檚.

Changes in the brain that occur during menopause so closely resemble those seen in 础濒锄丑别颈尘别谤鈥檚 that some researchers suggest it may signal the start of the disease.

鈥淲e are trying to find out what happens at that particular time that puts brains at risk,鈥� says , a neuroscientist studying 础濒锄丑别颈尘别谤鈥檚 at the University of Southern California who has turned her attention to the menopause.

That knowledge might lead to new ways to help women deal with the unpleasant symptoms of the menopause. Even better, it is possible that therapies to artificially boost hormone levels could protect the brain from these changes altogether 鈥� potentially staving off the ravages of dementia later in life.

The menopause essentially signals the end of a woman鈥檚 ability to have children. As the number of eggs inside the ovaries dwindles, the amount of oestrogen they produce plummets, too. It is the lack of oestrogen 鈥� and possibly some of the other hormones released by the ovaries 鈥� that is thought to trigger the common symptoms of menopause. These can include hot flushes, fatigue, weight gain, lack of sex drive, and vaginal dryness.

But cognitive effects such as mood swings, insomnia, anxiety and forgetfulness are still often overlooked. This is partly because they may be seen as going hand in hand with ageing. 鈥淎nother potential reason is that the cultural expectation is that women just endure, even if they may be experiencing uncomfortable or disturbing symptoms,鈥� says Brinton.

The brain has plenty of oestrogen receptors, so there鈥檚 nothing new in the idea that a dive in levels of the hormone can have an effect. But until relatively recently, any impacts on the brain were thought to be associated with reproduction 鈥� things like attraction and sex behaviours.

Then an explosion of research over the past decade revealed that a drop in oestrogen on memory, mood and even brain health in both men and women.

鈥淎 fall in oestrogen levels seems to change the type of energy the brain uses鈥�

These findings raised a red flag with Brinton, who has been trying to understand why women are more susceptible to 础濒锄丑别颈尘别谤鈥檚 disease. 鈥淚 realised it might be the hormonal transition in perimenopause and menopause that appears to be the kick-starter for 础濒锄丑别颈尘别谤鈥檚 in some women,鈥� she says.

This idea also fits with findings from Brinton and others that oestrogen has a protective function on the brain. One form of oestrogen called oestradiol, for example, ramps up activity in the brain cells鈥� mitochondria 鈥� essentially, their energy factories. The extra energy boost helps cells recover from damage associated with the normal wear-and-tear of ageing.

鈥淵ou can imagine that if there is this drop in oestrogen, the brain becomes more sensitive to damage, and that could lead to the death of neurons,鈥� says neuroscientist at the University of Queensland in Australia, who studies the ageing brain.

And a fall in oestrogen levels doesn鈥檛 just cause the brain to produce less energy, it also seems to change the type of energy it uses.

For most of our lives, the brain鈥檚 fuel of choice is glucose. 鈥淭he brain is the most glucose-dependent organ in the body,鈥� says Brinton. At least, it is until menopause hits. Brinton has found that, as mice go through their equivalent of menopause, the amount of glucose metabolised by their brains drops dramatically, by about 25 per cent.

Hungry brain

When body tissues are faced with a shortage of glucose, they enter a 鈥渟tarvation response鈥�, and turn to fats as a backup source of energy. Something similar seems to happen in the brain. Over time, it appears that the brain resorts to a readily available source of fats 鈥� myelin, the fatty white sheaths that coat the majority of brain cells and ensure that brain signals travel quickly. 鈥淲e have found that the brain will catabolise the white matter for fuel,鈥� says Brinton. In short, the brain starts to eat itself.

Most of Brinton鈥檚 research has been in mice, but in work yet to be published, she and her colleagues have suggesting that something similar happens in the brains of some women going through the menopause. 鈥淲e see that there is a decline in glucose metabolism, a change in white matter volume and grey matter volume, and an increase in beta amyloid production relative to men,鈥� she says.

This switch could account for some of the symptoms of menopause. For instance, fatty molecules are a much less efficient energy source than glucose, and their metabolism is known to create a lot more heat. Animal studies suggest this could trigger hot flushes. But could these changes also signal the start of 础濒锄丑别颈尘别谤鈥檚 disease? Two-thirds of people with 础濒锄丑别颈尘别谤鈥檚 are women. And although most are diagnosed in their 70s, we know that the disease starts to develop around 15 to 20 years before symptoms start to show 鈥� which is when the menopause occurs.

Research in people with 础濒锄丑别颈尘别谤鈥檚 disease backs up the idea. Using a type of brain scan that measures how much glucose is being metabolised across different brain regions, in 2005 Lisa Mosconi at New York University and her colleagues found that reduced glucose metabolism is a hallmark of .

鈥淟isa and I had a conversation, after which she went back and looked at her dataset for women who were perimenopausal or postmenopausal,鈥� says Brinton. 鈥淗er findings completely match our animal work 鈥� that there is a decline in glucose metabolism with the menopause.鈥� Last year, Brinton was awarded a to further research the link between the menopause, the ageing brain and 础濒锄丑别颈尘别谤鈥檚.

If a lack of oestrogen might cause so many problems for the brain, it makes sense to replace it in menopausal women. 鈥淚f we are going to intervene in 础濒锄丑别颈尘别谤鈥檚 disease, we鈥檙e much more likely to be successful if we identify women at risk at the time that these mechanisms are at play,鈥� says Brinton. 鈥淧erhaps we can change the risk.鈥�

Some studies do suggest that hormone replacement therapy (HRT), which was a popular treatment in the 1980s and 1990s, stave off dementia. But the theory was dealt a massive blow by the results of the 鈥� a huge trial of HRT in 7500 women in 2005.

It found that HRT actually seemed to hasten cognitive decline and increase dementia risk. It also suggested HRT put women at an increased risk of breast cancer and cardiovascular disease. The study was halted and the treatment鈥檚 reputation was left in tatters.

But the study was flawed. For a start, the women in the trial were given a formulation of hormones called conjugated equine oestrogens. 鈥淭hey have about 10 active oestrogens, and they come from pregnant horses,鈥� says at the University of Virginia in Charlottesville, who is executive director of the North American Menopause Society. Beyond the fact that humans are very different from horses, the hormonal milieu associated with pregnancy is far removed from that of a pre-menopausal woman.

What鈥檚 more, all the women in the study were over 65 鈥� well past the menopause. By this age, it is likely that the brain has adapted to low levels of oestrogen, and that the number of oestrogen receptors has diminished.

This could mean there is an optimum time for HRT treatment, during which the benefits could outweigh the risks. 鈥淭he hypothesis is that there is a limited window in which the brain is responsive,鈥� says Pinkerton. 鈥淚f there is too long a gap between symptoms and treatment, there won鈥檛 be an effect.鈥� That鈥檚 because HRT seems to work better on healthy brain cells 鈥� once they become sickly, they are too far gone to be rescued. This theory chimes with more suggesting that HRT seems to be, on the whole, beneficial for women who take it around the time of menopause.

But this doesn鈥檛 mean HRT should be prescribed for all women going through it. For a start, not everyone experiences unpleasant symptoms, and not all menopausal women eventually develop dementia 鈥� although Brinton would like to investigate whether there is a link between the severity of cognitive symptoms and later onset of dementia.

Increasing your lifetime exposure to these hormones is also known to increase the risk of breast cancer, especially in people who are already vulnerable. 鈥淚f used in the long term, we see an increase of just under one case per 1000 cases of breast cancer,鈥� says Nick Panay, a consultant gynaecologist and board member of the International Menopause Society.

Yet women shouldn鈥檛 feel afraid to try HRT if they are experiencing unpleasant symptoms, says Pinkerton. 鈥淲e used to recommend 鈥榯he lowest dose for the shortest amount of time鈥�, but it is important that we allow the treatment to be appropriate.鈥� Exactly what makes for the most appropriate treatment for any individual woman is still being figured out.

An altogether better solution might be to use oestrogens that only work on specific organs. A hormone that protects the brain but bypasses the breast, for example. 鈥淭hese drugs are already in development,鈥� says at Oregon Health and Science University in Portland. 鈥淭hey are definitely the future [of menopause treatment].鈥�

鈥淒rugs that target specific organs are the future of menopause treatment鈥�

It鈥檚 possible a nutritional approach may also protect the brain from these changes, says Brinton. 鈥淗ere the idea is for the brain to use lipids that are fed to you,鈥� she says. Such ketogenic diets, as they are known, have already been some people with epilepsy. But a high-fat diet might not be the best option for people who are already at risk of weight gain. Nor does it fit with evidence that a healthy Mediterranean-style diet rich in fruits, vegetables and grains has a positive impact on brain health. Keeping active, in contrast, has no downsides and can also counter menopausal symptoms, says Pinkerton. For instance, we know that exercise can boost mood and cognition and can increase bone mass.

Still, Brinton believes the best hope for treating menopause symptoms 鈥� and potentially staving off 础濒锄丑别颈尘别谤鈥檚 鈥� will be individually tailored hormone therapies given at exactly the right time. 鈥淲e are in an age where we can bring a precision medicine approach to hormone therapies,鈥� she says. 鈥淲e can start to ask questions about what hormone therapies are best for particular women. That鈥檚 the exciting new frontier for women鈥檚 health in latter years.鈥�

This article appeared in print under the headline 鈥淐hanging your mind鈥�