Research questions:
1. Do males and females exhibit distinct biological profiles associated with brain ageing and dementia risk?
2. Do sex-specific factors, such as menopause, menarche and exogenous hormone use, explain the divergent biological profiles in brain ageing and dementia?
3. Do genetics, cardiometabolic factors, and medication use drive sex differences in these biological mechanisms related to brain ageing and dementia?
4. Can we develop sex-specific predictive models for brain ageing and dementia?
Objectives:
1. Characterize sex differences in biological signatures (blood biochemistry, proteomics, metabolomics, neuroendocrine markers) associated with brain ageing and dementia.
2. Examine the influence of sex-specific factors, genetics, cardiometabolic health, and medication use on these differences.
3. Identify key mechanistic pathways underlying sex-specific patterns in brain ageing and dementia risk.
4. Develop and validate sex-stratified predictive models integrating reproductive, genetic, cardiometabolic, medication, and biomarker data.
Scientific rationale:
Women bear a greater dementia burden, likely due to distinct biological and hormonal pathways rather than survival differences. Sex has often been treated as a confounder, limiting understanding of its mechanistic role. The UK Biobank’s rich dataset enables systematic identification of biological mechanisms driving sex differences in brain ageing and dementia.
By integrating female reproductive histories, menopause status, and hormone use, this project will clarify how these experiences influence dementia risk. It will also assess how sex-specific, genetic, cardiometabolic, lifestyle, and polypharmacy factors shape biological pathways via diverse biomarkers.
Finally, overall brain health will be assessed using a “brain age gap” metric, rather than focusing solely on dementia diagnoses.