A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry

African descent populations have a lower Alzheimer disease risk from ApoE epsilon 4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE epsilon 4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE epsilon 4 allele and the SNP rs10423769_A allele, (beta = -0.54,SE = 0.12,p-value = 7.50x10(-6)) in the discovery data set, and replicated this finding in Ibadan (beta = -1.32,SE = 0.52,p-value = 1.15x10(-2)) and Puerto Rican (beta = -1.27,SE = 0.64,p-value = 4.91x10(-2)) individuals. The non-Hispanic Whites analyses showed an interaction trending in the protective direction but failing to pass a 0.05 significance threshold (beta = -1.51,SE = 0.84,p-value = 7.26x10(-2)). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE epsilon 4/epsilon 4 carriers lacking the A allele to 2.1 for ApoE epsilon 4/epsilon 4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE epsilon 4 for developing Alzheimer disease. The mechanism of the interaction with ApoE epsilon 4 is not known but suggests a novel mechanism for reducing the risk for epsilon 4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

Automated summary

African descent populations have a lower risk of developing Alzheimer's disease compared to other populations due to a specific genetic variant. The study identified a new locus that reduces the risk effect of ApoE epsilon 4 on Alzheimer's disease in African ancestry populations.