Active Brain & Nervous System

Does menopause enhance Alzheimer’s Disease risk by exacerbating vascular dysfunction?

Funder Wellcome Charity-funded
Recipient organisation University of Sheffield
Funding £1.7M
Period Jul 2025 — Jul 2033

In plain English

AI plain-English summary

Women going through menopause face double the lifetime risk of developing Alzheimer’s disease compared to men, and this project tests whether the loss of oestrogen—which normally helps blood vessels widen—triggers vascular damage that makes the brain vulnerable to dementia. The problem is that hormone replacement therapy (HRT) has shown mixed results in clinical trials, partly because studies haven’t accounted for genetic factors like APOE4 status or when treatment begins. This research uses mice with induced menopause to isolate those variables. The team will image blood vessels in the living brain, run cognitive tests, and sequence RNA to see how menopause, APOE4, and age interact to impair vascular function. They will then test whether the timing of HRT matters, and whether alternative drugs that target vasodilatory pathways—identified from previous RNA sequencing—can restore healthy blood flow. Finally, they will check whether menopause accelerates the buildup of amyloid plaques, the hallmark of Alzheimer’s, in a mouse model of the disease. If the work succeeds, it could clarify why HRT helps some women but not others, and point toward more targeted treatments for preserving vascular health after menopause. This is fundamental science—it won’t immediately change clinical practice—but understanding the vascular link could eventually guide when and how to intervene to cut women’s Alzheimer’s risk.

View original technical description
The clinical burden of dementia falls primarily on females, whose lifetime risk for developing Alzheimer's disease (AD) is double males. Many risk factors for AD (e.g. APOE4) are shared with cardiovascular disease, and vascular dysfunction is observed early in neurodegeneration. Oestrogen promotes vasodilation and is depleted during menopause, which I predict contributes to female's unique susceptibility to AD. Hormone replacement therapy (HRT), the recommended treatment during menopause, aims to restore oestrogen, although clinical studies examining the impact of HRT on cognition and AD risk have been inconclusive. Limitations of previous studies include that variable genetic and lifestyle factors, including APOE status and the timing of HRT initiation, have not been accounted for. Using a preclinical mouse model with induced menopause, this project seeks to explore the impact of menopause, APOE status and age on vascular and cognitive health through in vivo imaging, behavioural testing, immunohistochemistry and RNAsequencing. Subsequently, relevant treatment options for improving vascular health will be explored by assessing the impact of the timing of HRT initiation, and alternative novel therapeutic options (identified through previous RNAsequencing) which target vasodilatory pathways impacted by menopause. Finally, the impact of menopause on amyloid plaque progression will be explored in an APP/PS1 model.

View the original record at the funder ↗

Researchers

Kira Shaw (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Menopausal transition and APOE4 mediated Alzheimer’s disease (AD) vulnerability
Enhancing cognition through the menopausal transition in at-risk 'APOE4' carriers by fatty acid and hormonal modulation.
Enhancing cognition through the menopausal transition in at-risk 'APOE4' carriers by fatty acid and hormonal modulation BB/X002209/1
Is Alzheimer's disease triggered by a failure of the brain's blood supply?
How do individual differences in midlife adiposity and APOE genotype as risk factors for dementia affect brain structure and cognition? A cross-sectional MRI study.

Original classification

Career Development Award

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