APOE and Cerebral Microbleeds: Insights Into Causal Proteins and Therapeutic Targets
Lei Yang, Jian‐Lan Zhao, Jie Song, Lin‐Hui Chen, Chun Yu, Qiang Yuan, Gang Wu, Jin Hu, Mei‐Hua WangAbstract
Background
Cerebral microbleeds (CMBs) are small chronic brain hemorrhages that can be linked to cognitive decline and stroke risk. Understanding the underlying genetic and proteomic mechanisms can enhance therapeutic interventions. This study aimed to explore the relationship between circulating proteins (cis‐pQTLs) and CMBs using Mendelian randomization (MR) and colocalization analysis, along with protein–protein interaction (PPI) network construction and the evaluation of lifestyle factors influencing CMB‐related proteins.
Methods:
A two‐sample MR approach was employed to investigate potential causal relationships between protein levels and CMB risk using cis‐pQTLs as instrumental variables. Colocalization analysis was conducted to assess whether the same genetic variants influence both circulating proteins and CMB susceptibility. Additionally, a PPI network was built to prioritize therapeutic targets, and drug efficacy was evaluated using known protein targets. A systematic MR analysis examined the impact of 17 healthy lifestyle factors on CMB‐related proteins.
Results:
MR analysis revealed an association between 79 plasma proteins and CMBs, with one protein remaining significant after false discovery rate correction. Colocalization analysis identified APOE as a causal protein for CMBs, supported by a strong posterior probability (PP4 = 0.996). PPI network analysis highlighted the potential bleeding risks of antithrombotic medications in CMB pathogenesis and Rosuvastatin. Furthermore, MR analysis showed that dietary factors, particularly cooked vegetable intake, were associated with APOE‐related pathways, though these findings warrant cautious interpretation regarding lifestyle modifications.
Conclusions
This study provides evidence for a causal relationship between circulating proteins and CMBs, with APOE identified as a key factor. The identification of coagulation‐related proteins highlights the potential risks of antithrombotic medications in CMB pathogenesis. Lifestyle factors may influence protein‐mediated CMB risk, suggesting avenues for future research into gene–environment interactions.