Cross-Tissue Proteomic Mendelian Randomization Identifies Therapeutic Targets for Vascular dementia

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Vascular dementia (VD) is a leading cause of dementia with no disease-modifying treatments.
• Genetically associated proteins in the brain, CSF, and plasma are promising therapeutic targets.
• A comprehensive proteome-wide screening for VD-associated proteins is lacking.

Purpose of the Study:

• To conduct a proteome-wide screening for VD-associated proteins using a cross-tissue Mendelian randomization framework.
• To identify causal proteins, explore metabolite-mediated effects, determine cell-type specificity, and prioritize therapeutics.
• To establish a framework for targeted therapeutic development in VD.

Main Methods:

• Cross-tissue proteomic Mendelian randomization (MR) integrating pQTL data (brain, CSF, plasma) with VD GWAS.
• Metabolomic MR to explore metabolite-mediated effects.
• Single-nucleus RNA sequencing (snRNA-seq) for cell-type specificity.
• Drug-target interaction analysis and molecular modeling for therapeutic prioritization.

Main Results:

• APOE identified as the strongest VD-associated protein in CSF and plasma, indicating systemic relevance.
• Several CNS-specific proteins (14-3-3 family, AREG, SMOC1, UBE2G2) exclusively associated in CSF.
• Metabolomic MR linked specific metabolites to APOE and VD progression; APOE upregulation observed in excitatory neurons.
• Benserazide and puromycin identified as top drug candidates.

Conclusions:

• Systematic identification of genetically validated proteomic targets for VD.
• APOE established as a central molecular driver of VD.
• Integrated framework combining multi-omics and drug discovery supports precision medicine for VD.