APOE ε4

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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.

Differences in Ancestry Affect the APOE ε4 Gene and Alzheimer’s Disease Risk

Ancestry-related Differences in Chromatin Accessibility and Gene Expression of APOE ε4 Are Associated with Alzheimer’s Disease Risk

In this study, we explored why the APOE ε4 gene increases Alzheimer’s disease risk more strongly in people with European ancestry than in those with African ancestry. We analyzed brain tissue from individuals with Alzheimer’s disease who all carried two copies of APOE ε4 but differed in their local genetic ancestry around the APOE gene. Our results showed that APOE ε4 was more active in brains with European local ancestry, especially in astrocytes, a type of support cell in the brain. We found that this increased activity was linked to greater chromatin accessibility, meaning the DNA near APOE ε4 was more open and easier to turn on in European ancestry brains. These ancestry-related differences were not limited to APOE alone but extended across the genome. Genes with increased accessibility in European ancestry astrocytes were involved in processes such as synaptic function, cholesterol handling, and astrocyte reactivity. In the discussion, we suggest that these molecular differences help explain why APOE ε4 confers higher Alzheimer’s disease risk in people with European ancestry compared to those with African ancestry. Our findings highlight that genetic risk depends not only on which variant a person carries, but also on ancestry-specific regulation of gene activity. This work underscores the importance of studying multiple ancestries to fully understand Alzheimer’s disease biology and to ensure that genetic insights are relevant to all populations

Rajabli F, Seixas AA, Akgun B, Adams LD, Inciute J, Hamilton KL, Whithead PG, Konidari I, Gu T, Arvizu J, Golightly CG, Starks TD, Laux R, Byrd GS, Haines JL, Beecham GW, Griswold AJ, Vance JM, Cuccaro ML, Pericak-Vance MA. African Ancestry Individuals with Higher Educational Attainment Are Resilient to Alzheimer’s Disease Measured by pTau181. J Alzheimers Dis. 2024;98(1):221-229. doi: 10.3233/JAD-231116. PMID: 38393909; PMCID: PMC11091636.

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