How menopause radically changes the brain – and what happens after

From brain fog to anxiety, the cognitive impacts of menopause are familiar to many. But now it seems the brain changes are much more profound than previously imagined, with potentially long-term effects perhaps even explaining why women are at a greater risk of Alzheimer’s disease.

The changes are so dramatic, says Roberta Brinton at the University of Arizona, who studies the female brain, that they are akin to a home renovation: “It becomes a different brain.”

These discoveries underscore the ways in which midlife can influence brain health in older age – and highlight the brain’s remarkable resilience.

“The menopausal transition can unmask neurological vulnerabilities,” says Brinton. “For these women, menopause is a critical period for both identifying neurological risks and intervening appropriately.”

Menopause occurs once menstruation permanently ends, usually around age 50. Ovaries stop producing substantial amounts of the reproductive hormones oestrogen and progesterone, triggering widespread symptoms including sleep disturbances, hot flushes and mood swings.

These symptoms can begin in the decade before menopause – a period known as perimenopause, which is characterised by dramatic fluctuations in oestrogen. This tumult has a profound effect on the female brain, which relies on oestrogen for various functions. The hormone plays an essential role in converting glucose into energy, contributing up to 25 per cent of the brain’s energy production. When oestrogen plummets, “the brain undergoes a bioenergetic crisis”, says Brinton.

This energy crisis can be seen in brain-imaging studies. In 2021, Brinton and her colleagues used MRI to scan the brains of 161 women between the ages of 40 and 65. Thirty participants were premenopausal (the time before the perimenopause), 74 were postmenopausal, while the rest were in perimenopause.

On average, glucose metabolism – the conversion of glucose into energy – was roughly 20 per cent lower for women who were postmenopausal compared with those who were premenopausal in areas of the brain associated with memory, speech perception and the processing of visual and auditory information. In women who were perimenopausal, it was about 10 per cent lower.

Research in animals suggests the brain makes up this energy deficit by turning to an alternative fuel source: fatty compounds known as lipids. The menopausal brain “goes to its local ATM of lipid, which is the white matter of the brain”, says Brinton.

White matter acts as the brain’s communication network, speeding up the transmission of messages between different regions. It makes up roughly half the organ and is composed of nerve fibres coated in a substance made of lipids.

In Brinton’s study, the volume of white matter in the brain’s anterior and posterior regions was around 10 per cent lower during postmenopause than premenopause. The difference was significant even after accounting for age, which is also associated with declining white matter, suggesting that the menopausal brain turns to lipids for fuel.

Given that white matter volume declines in Alzheimer’s disease, too, these findings suggest that menopause may lay the groundwork for the condition, says Brinton. It may also explain why two-thirds of Alzheimer’s cases are in women and why those who enter menopause earlier are at even greater risk.

Other scientists are sceptical of the idea that the menopausal brain essentially cannibalises itself for fuel. In the first-ever long-term study of the menopausal brain, Pauline Maki, a psychologist and women’s health specialist at the University of Illinois Chicago and her colleagues are scanning the brains of 242 women between the ages 40 and 60. Early results presented at a conference last year found no difference in brain volume, including white matter volume, between brains that had not yet gone through perimenopause or menopause and those that were postmenopausal.

The same was true for a subset of 35 women who underwent brain scans while in different stages of the menopausal transition. However, Brinton says the discrepancy could come down to other factors, such as differences in the study population. We won’t know for sure until the findings are published, which should happen later this year.

Even if the results hold up, that doesn’t mean the brain goes unchanged. Numerous studies show that oestrogen loss affects the ability to learn and remember verbal material, particularly in perimenopause. “Those abilities are exquisitely sensitive to the loss of oestrogen,” says Maki.

Yet the impacts rarely reach cognitive impairment. Studies show that around 9 in 10 women in perimenopause score within the normal range on verbal memory tests. “It is not like they are developing dementia,” says Maki. “But there is a loss.”

In a paper published last year, Maki and her colleagues analysed the brain activity of nearly 200 women who were postmenopausal as they carried out memory tasks. Higher oestrogen levels were not only associated with better performance, but also with greater activation in the temporal lobes and the frontal cortex, both of which are important for memory. In a separate, yet-to-be published study, she and her colleagues also linked lower oestrogen levels to weaker connectivity between the hippocampus and prefrontal cortex in postmenopausal women performing memory tasks.

These findings probably explain why hormone replacement therapy (HRT) – the effects of which include restoring oestrogen levels – can improve cognition in women during perimenopause. Other research has associated the treatment with a lower risk of Alzheimer’s disease, although timing is key. Most studies suggest that the protective effects of HRT are seen in those who begin treatment up to 10 years before their final period, meaning it may be important to start soon after symptoms begin.

It is possible that introducing oestrogen early prevents the brain from turning to white matter for fuel, says Brinton, but it might be too late to have an effect once that shift has taken place.

HRT also reduces hot flushes, which can be incredibly disruptive for sleep. “And you don’t need me to tell you that chronic sleep deprivation can be toxic to the brain,” says Maki.

Maki and her colleagues similarly found that using local anaesthetic to inhibit a neural structure involved in temperature regulation in the spinal cord improves verbal memory in women during menopause. And Brinton and her colleagues have developed a non-hormonal medication, which acts on oestrogen receptors to reduce hot flushes and potentially even Alzheimer’s risk. It is currently in phase II clinical trials.

The good news is that, even without HRT, the brain appears to adapt. Numerous pieces of research, including a brain-imaging study from this year of nearly 11,000 women, show that the amount of grey matter – which harbours neuronal connections in the brain – is lower in perimenopause than it is in premenopause. Yet Brinton’s 2021 study showed that grey matter loss seems to rebound in some areas after menopause.

Research has also found no differences in memory task performance between women during premenopause and postmenopause, and those in the latter group seem to show greater activation of the dorsolateral prefrontal cortex, which is involved with memory. The brain seemingly adapts to hormonal changes by recruiting additional brain circuits to compensate.

Even so, the transition may enhance Alzheimer’s risk for some, says Maki, which is why it is so important to minimise other risk factors, such as high blood pressure or hearing loss.

Despite the radical brain changes brought about by menopause, long-term cognitive issues are far from inevitable. “All [women] go through menopause. We certainly don’t all develop dementia, and we certainly don’t all continue to experience brain fog,” says Maki. Indeed, the brain’s transition through menopause is a sign of the organ’s immense capacity to rebuild. “Clearly, the brain adapts to the change,” she says.