Rationale for Correct Answer

The correct answer is: People with African ancestry may inherit gene regions around the ApoE allele that reduce ApoE4 expression

Carrying the ApoE4 allele increases the risk for LOAD in all populations,1 but the magnitude of this effect varies across populations.2 Japanese populations have a higher risk from the ApoE4 allele, and people of African descent have a lower risk.3 The effect size of disease-associated loci acting on ApoE is also inconsistent across populations and may explain the lower ApoE4 risk in African populations. Research suggests that inheriting the genomic region around the ApoE gene from an African ancestor is linked to a smaller ApoE effect on Alzheimer's disease than if it is inherited from a European ancestor.4 R145C variant found only in people of African descent can be found on the ApoE3 allele and triples LOAD risk only in combination with an ApoE4 allele.5 ApoE gene frequency also varies significantly across populations.2 The molecular mechanisms and pathways leading to LOAD are relatively conserved across populations. However, the disease-associated loci within these pathways differ.6

1. Farrer LA et al. JAMA. 1997;278:1349-1356.
2. Jia L et al. Alzheimers Dement. 2020;16:1613-1623.
3. Rajabli et al. PLoS Genet. 2022;18:e1009977.
4. Rajabli F et al. PLoS Genet. 2018;14:e1007791.
5. Le Guen Y. et al. JAMA. 2023;329:551-560.
6. Kunkle BW et al. JAMA Neurol. 2021;78:102-113.