Abstract Body: Introduction: Coagulation factor XI (FXI) inhibitors have shown a better safety profile than other anticoagulants, offering similar reductions in ischemic stroke (IS) risk with a lower risk of intracerebral hemorrhage (ICH). The APOE ε4 genotype is associated with increased risks of both IS and ICH, likely due to its effects on lipid levels, intracranial atherosclerosis, and cerebral amyloid angiopathy. We hypothesized that APOE ε4 carriers would gain greater therapeutic benefit from genetically reduced FXI levels compared to non-carriers.

Methods: We conducted a two-stage Mendelian randomization (MR) analysis using the random-effects, inverse-variance weighted method. First, we estimated the effect of genetically proxied FXI inhibition on IS and ICH risk in the general population using summary data from genome-wide association studies of FXI levels (16,169 participants), IS (1,503,898 controls and 110,182 cases), and ICH (3,745 controls and 3,226 cases). Second, we performed stratified analyses to estimate the effect of genetically determined FXI levels on IS (10,343 cases and 476,838 controls) and ICH (2,236 cases and 484,945 controls) risk across APOE ε4 carriership strata (0, 1, or 2 alleles) using UK Biobank data.

Results: In the general population, random-effects, inverse-variance weighted MR analyses showed that every 1 unit decrease in natural log-transformed FXI levels was associated with a 37% reduction in IS risk (OR:0.63; 95%CI:0.52–0.77; p<0.001) without a significant increase in ICH risk (OR:0.86; 95%CI:0.37–2.00; p=0.73). Stratified MR analyses indicated that genetically determined reductions in FXI levels had varying protective effects on IS risk based on APOE ε4 status: 31% in non-carriers (OR:0.69, 95%CI:0.53–0.91; p=0.008), 43% in carriers of 1 allele (OR:0.57, 95%CI:0.36–0.91; p=0.02), and 75% in carriers of 2 alleles (OR:0.25, 95%CI:0.06–1.06; p=0.06). Similar MR analyses showed no significant increase in ICH risk with genetically determined reductions in FXI levels in any APOE ε4 strata (all p>0.38, Figure 1).

Conclusion: This two-stage genetic study provides causal evidence that lower FXI levels reduce IS risk in the general population, with an even stronger effect among APOE ε4 carriers, while not increasing ICH risk. These results indicate that FXI inhibitors might be a safer and more effective alternative to other anticoagulants among APOE ε4 carriers, who are known to be at higher risk for both ischemic and hemorrhagic events.