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Beginning hormone replacement therapy (HRT) within five years of menopause onset appears to lower the risk of Alzheimer’s disease. Yet starting it later in life seems to have the opposite effect, suggesting the timing of HRT influences how it affects the brain.

Women have an increased risk of developing Alzheimer’s disease compared with men, especially after going through menopause. This may be due to declines in the hormone oestrogen, which regulates energy production and inflammation in the brain. As such, HRT has emerged as a potential tool for mitigating Alzheimer’s risk after menopause. But studies on its effectiveness have shown mixed results.

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So at Pandit Bhagwat Dayal Sharma University of ��ҹ����1000���� Sciences in India and his colleagues analysed incidences of Alzheimer’s disease across 53 studies, totalling more than 8.4 million people. All of the participants were post-menopausal.

They found in randomised-controlled trials, participants on HRT had, on average, a 38 per cent greater risk of developing Alzheimer’s than those who weren’t. But that wasn’t the case with observational studies, which showed a 22 per cent lower risk of Alzheimer’s disease among those taking HRT.

Vaibhav, who presented these results on 15 September at a meeting of the American Neurological Association in Maryland, says the stark contrast probably comes down to age. Most participants in the randomised-controlled trials were 65 years or older, whereas those in observational studies tended to be younger, he says. Further analysis showed, on average, those who started HRT within five years of menopause had a 32 per cent lower risk of Alzheimer’s disease across follow-up periods that ranged from five years in some studies to a person’s lifetime until death in others.

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“This menopausal transition is actually a neurological transition,” says at the University of Arizona, who wasn’t involved with the research. As oestrogen levels drop, the brain must find new ways of producing energy. Some evidence suggests the brain may cannibalise itself, using compounds important for maintaining brain function as fuel, potentially driving neurodegeneration. Initiating HRT during menopause or soon after may stop this shift, says Brinton. But if the brain has already made this transition, it may be too late for HRT to have an effect, she says.

“We need more studies to find out the solution to this confusion,” says Vaibhav. Without a clearer understanding of HRT’s effects, “women might be missing out on the benefits, or women might be at harm”, he says.