Alzheimer’s disease (AD) exhibits a pronounced sex difference: even after age adjustment, women show significantly higher incidence and prevalence than men. This disparity cannot be fully explained by lifespan, suggesting underlying biological mechanisms. However, most existing studies remain descriptive and cannot distinguish whether observed molecular differences represent causal drivers, disease consequences, or sex-specific causal pathways.
This project aims to elucidate the biological and systemic factors underlying sex differences in AD by integrating genomic, hormonal, and metabolic data from the UK Biobank. Four key mechanisms will be investigated:
1. X-chromosome-linked gene expression and its downstream impact on neurodegenerative pathways;
2. Sex hormone dynamics and their effects on metabolic reprogramming, particularly across the menopausal transition;
3. Comorbidities (such as diabetes, hypertension, hyperlipidaemia, and polycystic ovary syndrome) as external modulators of sex-dependent molecular expression and epigenetic regulation;
4. DNA methylation abnormalities and their interaction with genetic and metabolic factors (such as ApoE4, sorl1 mutation and so on) contributing to AD susceptibility.
Using longitudinal multi-omics and clinical data, we will conduct genome-wide sex-interaction analyses to map sex-specific causal molecular networks. Mendelian randomization (MR) will be applied to establish time-dependent causal effects of hormonal and metabolic traits on AD progression. We will further construct sex-stratified multi-omics causal networks and perform drug-target MR analyses to prioritise therapeutic targets with sex-dependent efficacy.
The findings will clarify the biological basis of sex-specific vulnerability to AD and support the development of precision prevention and treatment strategies tailored for males and females.
Estimated duration: 3 years
