A UK Biobank GWAS study (1,016 postoperative delirium cases, 139,148 controls) identified seven SNPs associated with postoperative delirium after major surgery (p < 5 × 10⁻⁸), mapping to four genes including APOE. The leading SNP rs429358 is an APOE missense variant. Five SNPs remained significant after excluding existing dementia and two after excluding subsequent dementia. Genetic correlation analyzes showed a shared genetic architecture with Alzheimer's disease (rho 0.68, 95% CI [0.46, 0.81]; p < 0.001). APOE ε4 allele increases risk dose-wise: odds ratio 1.75 (95% CI [1.53, 2.0]) for one copy and 4.19 (95% CI [3.25, 5.41]) for two copies (p < 0.001 after adjusting for age and sex). Limitations include clinical case coding and limited statistical power for small genetic effects. The findings suggest a shared genetic liability with Alzheimer's disease via APOE.