To identify proteins mediating the effect of APOE ε4 on intracerebral hemorrhage (ICH) risk using genomic and proteomic integration to elucidate mechanisms and therapeutic targets.

Carriers of the APOE ε4 allele have a higher risk of ICH than non-carriers. APOE ε4 also substantially increases the likelihood of amyloid-related imaging abnormalities and ICH in Alzheimer’s disease patients on anti-amyloid therapy. The molecular intermediaries of this genetic predisposition are unknown.

Data from 52,560 UK Biobank participants with genomic and proteomic data (mean age 56.8, 46% female) were analyzed. APOE ε4 carriership was modeled dominantly (0 vs.1 or 2 alleles). The analysis comprised 5 subsequent steps: (1) linear regression of APOE ε4 against 2,923 plasma proteins; (2) testing resulting proteins for ICH association; (3) two-sample Mendelian Randomization (MR) to assess causality; (4) mediation analysis to quantify their contribution to the APOE ε4-ICH relationship; (5) MR with other ICH-related outcomes. Analyses adjusted for age, sex, and genetic principal components and controlled for false-discovery rate.

Of 11 proteins passing steps 1-2, only Paralemmin-1 (PALM) satisfied both MR (inverse-variance weighted OR 1.47, 95% CI 1.18-1.80) and mediation criteria. PALM accounted for 16% of the total effect of APOE ε4 on ICH risk (P=0.007). In further MR analyses, PALM was also associated with microbleeds, white matter hyperintensities, and white matter integrity measures (fractional anisotropy, mean diffusivity), suggesting a role in amyloid-related small vessel disease and perivascular dysfunction.

This proteogenomic approach pinpointed PALM as potential mediator linking APOE ε4 to ICH. PALM organizes neuronal and endothelial inner membrane cytoskeleton scaffold supporting junctional integrity and tissue resilience. APOE ε4 causes vascular amyloid deposition, blood-brain barrier damage, and impaired perivascular clearance. Dysregulation of PALM-dependent scaffolding offers a coherent mechanism for small vessel fragility and hemorrhage. These findings suggest PALM-centered pathways as actionable targets mitigating ICH risk in APOE ε4 carriers.