Large-scale genomic studies identified more than 20 modest-effect Alzheimer disease (AD) risk loci besides the APOE gene.^1-8 However, these studies were predominantly conducted in individuals of non-Hispanic White ancestry and, taken together, the identified loci explain only 30% to 40% of the genetic contribution to AD,^9,10 substantially less than the heritability estimates from twin studies ranging from 60% to 80%.¹¹ Compared with non-Hispanic White individuals, African American individuals from the same community are twice as likely to develop AD.¹² Supporting the notion that there are many genetic loci with small effect sizes contributing to these observed ancestral differences in disease risk, we recently demonstrated that AD cases in African American individuals show higher levels of African ancestry than unaffected individuals, both globally and locally at AD-relevant loci.¹³

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome (“global” ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles (“local” ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors. The strongest risk gene identified for late-onset Alzheimer disease is ApoE. However, the risk for Alzheimer disease due to ApoE is not consistent across populations. For example, individuals with African ancestry experience less risk from ApoE ε4 than individuals of European or Asian ancestry. The cause of the difference in risk effect is currently unknown. This has led us to ask: What is/are the factor(s) contributing to the risk effect variation of ApoE across the populations? We hypothesized two possibilities for the variability of ApoE risk: 1) ethnic-related environmental factors that vary across populations, such as diet and lifestyle activities, or 2) a population-specific genetic difference in the ApoE gene, or in its surrounding region. We tested our hypothesis using populations with more than one genetic ancestral background, specifically African Americans and Puerto Ricans. Our study showed that the risk of Alzheimer disease is lower for individuals who inherited the genomic region surrounding the ApoE gene from an African ancestor than it is for risk allele carriers who inherited the region from a European ancestor. These findings suggest that protective genetic variant(s) most likely lie(s) within the genetic region surrounding the ApoE gene on the African ancestral background.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

African descent populations have a lower Alzheimer disease risk fromApoEε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding theApoElocus (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 theApoEε4 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 theApoEε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10^-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10^-2) and Puerto Rican (β = -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 (β = -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 forApoEε4/ε4 carriers lacking the A allele to 2.1 forApoEε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of theApoElocus, 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 ofApoE ε4for developing Alzheimer disease. The mechanism of the interaction withApoEε4is not known but suggests a novel mechanism for reducing the risk forε4carriers opening the possibility for potential ancestry-specific therapeutic intervention.