We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95% CI 3.2–12.7, P = 1.83 × 10−3) and ~ 7.6 years (95% CI 3.3–11.8, P = 8.69 × 10−4), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. Here, ASTN2 is linked to Alzheimer disease.