Oestrogen loss in brain tissue may help explain memory decline after menopause and women’s higher Alzheimer’s risk, a preclinical study suggests.

The findings suggest females may be especially sensitive to the loss of brain oestrogen in old age.

Scientists said the work could point to future treatments focused on restoring the brain’s supportive environment before memory loss develops.

Dr Hong Zhao, research professor of obstetrics and gynaecology in the division of reproductive science in medicine at Northwestern University Feinberg School of Medicine, said: “This study tells us that females, but not males, may be uniquely sensitive to loss of brain oestrogen at old age, potentially contributing to an increased risk of Alzheimer’s disease.”

Researchers at Northwestern University studied young and old male and female mice, with and without loss of brain oestrogen.

The study focused on the extracellular matrix, or ECM, a network of molecules in the space between brain cells. It helps support communication between cells and is important for memory, brain development and brain health. The ECM makes up nearly 20 per cent of the brain’s volume.

The ECM is especially abundant in the hippocampus, a part of the brain involved in learning and memory.

Scientists found that oestrogen loss, ageing and female sex were closely linked to changes in the ECM. The study is the first to examine oestrogen loss in the ECM.

The findings may help explain why women are at higher risk of Alzheimer’s disease, although the research was carried out in mice and further work is needed to understand whether the same mechanisms apply in humans.

Nearly two-thirds of people with Alzheimer’s disease in the US are women, but the reasons for this higher risk remain unclear.

Scientists have long suggested that falling oestrogen levels after menopause may reduce the brain’s natural protection against memory loss and neurodegeneration. Neurodegeneration means the gradual damage or loss of nerve cells in the brain.

Dr Serdar Bulun, chair of the department of obstetrics and gynaecology at Feinberg and a Northwestern Medicine physician, said: “We have provided some of the most compelling evidence that oestrogen is so important for memory function and other mood functions in the female brain.

“This should motivate clinicians to be more aware of the essential role of oestrogen for women’s brains, because once memory is gone, it’s gone.”

Before menopause, the ovaries are the main source of oestrogen in women. After menopause, oestrogen levels drop sharply, and only small amounts are produced in other parts of the body, including the brain, fat tissue, bone, muscle, blood vessels and breast tissue.

In mice, oestrogen is produced locally in the brain and gonadal fat in males, whereas in females it is produced mainly in the brain.

Research has shown that women with Alzheimer’s disease may have even lower oestrogen levels in the brain than women without the disease. The study further supports that.

The researchers used genetically engineered mouse models that lacked aromatase, an enzyme needed to produce oestrogen, either throughout the whole body or only in the brain.

They examined how the loss of oestrogen affected memory, behaviour and social function in male and female mice at young and old ages.

They also analysed changes in gene expression across the entire genome in the hippocampus in mice with brain-specific oestrogen loss at young and old ages in both sexes.

The authors said the findings suggest the ECM could become a target for future treatments.

Current Alzheimer’s treatments such as lecanemab and donanemab are designed to remove amyloid, an abnormal protein build-up in the brain that is one of the main signs of the disease.

However, researchers said it is still unclear how much these treatments help to slow memory loss or improve everyday functioning. Some studies suggest small benefits, while others show little meaningful improvement.

The study suggests a different approach could focus on restoring the brain’s supportive environment to help protect memory.

Zhao said: “Our findings will hopefully motivate future studies to better understand how this matrix is altered in postmenopausal women, and how it could potentially induce susceptibility to Alzheimer’s disease.”

Hormone replacement therapy, or HRT, has also been studied as a possible way to protect women from Alzheimer’s disease by restoring oestrogen levels.

However, clinical studies have produced mixed results, with some suggesting benefits for memory and cognitive function while others show little benefit or possible harm.

Zhao said differences may depend on the type of hormone treatment used, the age at which it begins and differences in study design.

She said: “More research is needed to understand how oestrogen affects the female brain and why oestrogen loss increases AD risk in women.

“Understanding these mechanisms could help researchers develop safer and more effective HRT strategies to prevent or slow the progression of AD in women.”