PhD: Alzheimer’s risk in women, menopause, apoe & exercise

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12/10/2025

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PhD
Oxford Road, Manchester M13 9PL
Posted 4 weeks ago

Website The University of Manchester

Closing date: 8th November

@manchester.ac.uk

PhD position, University of Manchester. Study how APOE genotype, menopause and exercise interact to influence vascular dysfunction and dementia risk in Alzheimer’s.

Changes in cerebral blood flow are among the earliest signs of Alzheimer’s disease, appearing years before cognitive symptoms and suggesting a role for vascular dysfunction in disease onset. This is especially evident in carriers of APOE4, the major genetic risk factor for late-onset Alzheimer’s, who show accelerated decline in blood flow during ageing before developing dementia. Females are disproportionately affected, with almost twice the lifetime risk of males (20% vs. 10%), accounting for around 65% of cases and showing worse outcomes and higher mortality. One likely driver of this sex-specific vulnerability is menopause, which causes a sharp loss of oestrogen, a key regulator of vascular function. Furthermore, the penetrance of APOE4 is modulated by sex. Female APOE4 carriers exhibit greater risk, faster cognitive decline, and increased Aß accumulation relative to males. Aß accumulation is also greater in peri- and post-menopausal women with the APOE4 genotype, suggesting oestrogen loss may exacerbate vascular vulnerability in APOE4 carriers, and reinforcing the importance of investigating hormonal and genetic interactions in AD risk.

Although female APOE4 carriers are at greater risk of developing Alzheimer’s disease, few studies have examined the shared vascular pathways through which APOE and menopause interact, or how lifestyle interventions might alter these risks. Hormone replacement therapy (HRT) is widely used to restore oestrogen levels, but its impact on dementia risk remains unclear. Some studies suggest HRT improves vascular function and cognition, even preserving brain volume in older APOE4 carriers, while others report negative effects on cognitive outcomes and Alzheimer’s risk. A key limitation is that most studies have not considered how genetic and lifestyle factors interact to shape dementia risk in women. Exercise represents an important candidate, as it is known to improve vascular health, may provide an alternative to HRT, and could differentially influence outcomes depending on APOE status and oestrogen levels.

This project will use APOE3 and APOE4 mice with induced menopause, and assess the impact of consistent exercise on cerebrovascular responses. Exercise levels will be manipulated by including an exercise wheel (or not) in the home cage. A cranial window will be inserted, and multi-photon imaging of blood vessels and corresponding excitatory neuronal calcium events will be studied to characterise functional hyperaemia, blood brain barrier leakage, vascular density and vasomotion. Cognition will be assessed using behavioural testing to measure activities of daily living, and spatial and working memory.

Entry Requirements

Applicants should hold (or be about to obtain) a First or Upper Second class (2:1) UK honours degree, or international equivalent, in a relevant subject.

Application Guidance

Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability.

Apply directly via this link: https://tinyurl.com/m87wpezv or on the online application portal, select MRC DTP PhD Programme as the programme of study.

You may apply for up to two projects within this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.

Please ensure that your application includes all required supporting documents: