Abstract A049: Proteogenomic Integration reveals Paralemmin-1 as a Mediator of Increased Intracerebral Hemorrhage Risk in APOE ε4 Carriers

Background: Carriers of the APOE ε4 allele have a higher risk of intracerebral hemorrhage (ICH) than non-carriers. Recent trial data further show that APOE ε4 substantially increases the likelihood of amyloid-related imaging abnormalities and subsequent ICH in Alzheimer’s disease patients on anti-amyloid antibody therapy. Yet, the molecular intermediaries of this genetic predisposition are unknown. Hypothesis: Genomic and proteomic data integration can identify proteins mediating the effect of APOE ε4 on ICH risk to elucidate disease pathophysiology and find potential therapeutic targets. Methods: 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 steps (Fig. 1): (1) linear regression of APOE ε4 against 2,923 plasma proteins; (2) testing proteins passing step 1 for association with ICH; (3) two-sample Mendelian Randomization (MR) of proteins from step 2 to assess causality; (4) mediation analysis of proteins with MR support to quantify their contribution to the ε4-ICH relationship; and (5) MR with other ICH-related outcomes. All steps were adjusted for age, sex, and genetic principal components and controlled for false-discovery rate. Results: 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, Fig. 2) and mediation criteria. PALM accounted for an estimated 16% of the total effect of APOE ε4 on ICH risk, indicating a significant indirect pathway ( P =0.007). In MR analyses with further outcomes, PALM was also associated with microbleeds, white matter hyperintensities, and white matter integrity measures (fractional anisotropy, mean diffusivity, Fig. 3), suggesting a role in amyloid-related small vessel disease and perivascular dysfunction. Conclusion: This integrative proteogenomic approach pinpointed PALM as potential mediator linking APOE ε4 to ICH. PALM organizes neuronal and endothelial inner membrane cytoskeleton scaffold that supports junctional integrity and tissue resilience. APOE ε4 causes vascular amyloid deposition, blood-brain barrier damage, and impaired perivascular clearance, therefore dysregulation of PALM-dependent scaffolding offers a coherent mechanism for small vessel fragility and hemorrhage. These findings suggest PALM-centered pathways as plausible, actionable targets mitigating ICH risk in APOE ε4 carriers.