A major UK study analysing data from nearly 125,000 women has found that menopause is associated with measurable changes in brain regions critical for memory, spatial navigation and emotional regulation,  the same areas that are affected early in Alzheimer’s disease.

The research, published this week in Psychological Medicine by Cambridge University Press, examined mental health, cognitive performance and brain structure in women before and after menopause, as well as among those who had used hormone replacement therapy (HRT).

“Menopause was associated with increased levels of anxiety, depression, and sleep difficulties,” the authors report, adding that structural brain changes were also evident. Specifically, “gray matter volumes in the medial temporal lobe (MTL) and anterior cingulate cortex (ACC)” were smaller in post-menopausal women compared to those who were pre-menopausal.

These regions play a central role in cognitive and emotional functioning. The medial temporal lobe includes the hippocampus and entorhinal cortex, which are essential for memory formation and spatial navigation, while the anterior cingulate cortex is involved in emotional regulation and cognitive control.

In their analysis of brain imaging data from 10,873 women, the researchers found that “MTL and ACC volumes were smaller in post-menopausal women compared to pre-menopausal women, with the lowest volumes observed in the HRT group.”

The authors note that gray matter loss in these regions has broader clinical relevance. Previous research has shown that “gray matter loss [is] known to be associated with cognitive decline,” while the ACC “is altered in mood disorders.”

The study draws on data from the UK Biobank, a large population cohort that includes health questionnaires, cognitive testing and MRI scans. After exclusions, the final sample comprised 124,780 women classified as pre-menopausal, post-menopausal women who had never used HRT, and post-menopausal women who had used HRT.

Mental health outcomes were a key focus of the research. The authors report that “menopause is linked to adverse mental health outcomes,” including higher levels of anxiety, depression and sleep disturbance. Contrary to expectations, HRT use did not appear to offset these challenges at a population level.

“Women using HRT reported greater mental health challenges than post-menopausal women not using HRT,” the study states. However, the researchers caution against a simple causal interpretation. Post-hoc analyses showed that “women prescribed HRT had higher levels of pre-existing mental health symptoms.”

As a result, the authors emphasise that the poorer outcomes observed in HRT users may reflect baseline differences rather than harmful effects of the therapy itself.

“Our findings suggest that menopause is linked to adverse mental health outcomes and reductions in gray matter volume in key brain regions,” the paper concludes. “The use of HRT does not appear to mitigate these effects and may be associated with more pronounced mental health challenges, potentially due to underlying baseline differences.”

The researchers say the results highlight “the unmet need for addressing mental health problems during menopause” and call for a better understanding of the neurobiological effects of hormonal changes during midlife.

While the study does not directly assess Alzheimer’s disease risk, the involvement of the medial temporal lobe and anterior cingulate cortex — regions known to be affected early in Alzheimer’s — underscores the importance of further research into how menopause-related brain changes may intersect with later-life cognitive decline.

“This study set out to investigate how [menopause and HRT] affect measures associated with women’s mental health, cognition, and brain structure,” the authors write, describing their work as “an extensive overview and quantification of the impact of menopause and HRT use.”

The article is published under an open-access Creative Commons licence and is based on one of the largest datasets to date examining menopause, brain structure and mental health in the general population.

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