ABCA7 deletion lowers age at onset of Alzheimer's disease and interacts with APOE ε4 synergistically in African‐ancestry populations

INTRODUCTION Apolipoprotein E ( APOE ) and ABCA7 genes are among the strongest heritable risk factors for Alzheimer's disease (AD) in African‐ancestry (AA) populations. APOE 𝜀4 affects both risk and age at onset (AAO), with lower risk in AA populations. This study evaluates the independent and interactive effects of the AA‐specific ABCA7 frameshift deletion and APOE 𝜀4 allele on AAO. METHODS We analyzed 3510 AA individuals, including AD cases and controls. Cox regression models assessed the effects of ABCA7 deletion, APOE genotypes, and their interactive influence on AAO. RESULTS APOE ε3/ε4 carriers with the ABCA7 deletion had a significantly shorter survival compared to ε3/ε4 carriers without the deletion. No significant differences were found between deletion carriers and non‐carriers with APOE ε3/ε3 or ε4/ε4 genotypes. DISCUSSION Our study showed that the ABCA7 deletion lowered the AAO of AD in APOE ε3/ε4 carriers from AA populations. These findings suggest that the AA‐specific ABCA7 deletion and the APOE ε4 allele have synergistic effects on AAO. Highlights AA‐specific ABCA7 deletion lowers AAO of AD in APOE ε3/ε4 carriers from AA populations. Findings suggest an interaction between ABCA7 deletion and APOE ε4 on AAO. APOE ε4 has a strong, dose‐dependent effect on AAO of AD in AA individuals. ABCA7 deletion impact on AAO of AD is stronger in females with APOE ε3/ε4.