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

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

The APOE gene is the strongest known genetic risk factor for Alzheimer disease (AD), first identified by Dr. Pericak-Vance and colleagues in 1993. The ε4 allele of APOE, a version of the gene, increases the risk of AD and is associated with an earlier age at onset, although its effect differs across ancestries.

Another important gene is ABCA7, particularly in individuals of African ancestry.  We previously identified a deletion, or missing segment of DNA, in ABCA7 that is specific to African-ancestry populations and is associated with an increased risk of AD. Because APOE and ABCA7 are both involved in lipid metabolism, which is important for brain health, we wanted to understand whether these two genetic factors might work together to influence when AD begins.

To answer this question, we studied 3,510 individuals of African ancestry, including African American and African participants from the DAWN Research project. Bringing these groups together allowed us to examine the effects of the ABCA7 deletion within a broader, global African-ancestry population.

We found that individuals who carried both one copy of the APOE ε4 allele and the ABCA7 deletion developed AD earlier than individuals who carried one copy of APOE ε4 but did not carry the deletion. The difference was approximately five years. These findings suggest that APOE and ABCA7 may interact to influence the age at onset of AD. Studying this type of gene-gene interaction can help us better understand the biological mechanisms that contribute to the disease.

The study also highlights the importance of global participation in AD research. Studying populations globally allows us to gain a more comprehensive view of the genetic architecture of AD and a better understanding of the biological mechanisms underlying the disease. By including participants from both the United States and Africa, this study provided a broader perspective on how genetic factors influence AD. Continued global collaboration will be essential for advancing diagnosis, prevention, and treatment approaches that can benefit people across all populations.

Akgun B, Gulyayev AV, Coker M, et al. ABCA7 deletion lowers age at onset of Alzheimer’s disease and interacts with APOE ε4 synergistically in African-ancestry populations. Alzheimers Dement. 2025 Aug;21(8):e70583. doi: 10.1002/alz.70583. PMID: 40832784; PMCID: PMC12365657.