Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations

Abstract

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.

Dissecting the role of Amerindian genetic ancestry andApoEε4 allele on Alzheimer disease in an admixed Peruvian population

“…The heterogenous risk effect of the ApoE gene across the populations is suggested to be correlated with the ancestral background local to the ApoE gene. Thus, to examine the ancestral background in our dataset we calculated the average ancestry proportions at the ApoE by taking the average of the local ancestry estimates around the ApoE gene (from 44 Mb to 46 Mb on chromosome 19) 15 . The pipeline to calculate the global and local ancestries was developed by our group using R and Python scripts.…”

“…The association of ApoE with AD risk differs between populations and is not clearly established in groups of Amerindian (AI) descent. The strongest association of ApoE and AD risk has been observed in East Asian (EA) populations (ε3/ε4 odds ratio OR: 3.1-5.6; ε4/ε4 OR: 11.8-33.1) followed by non-Hispanic White (NHW) populations (ε3/ε4 OR: 3.2; ε4/ε4 OR: 14.9) 8,9 . Its effect is weaker in African-descent and Hispanic populations (ε3/ε4 OR:1.1-2.2; ε4/ε4 OR: 2.2-5.7) [10][11][12][13][14] .Genetic studies examining the interaction of genetic ancestry and risk effect of the ApoE in Caribbean Hispanic populations (Puerto Rican and Dominican Republic) showed that the effect of the ε4 is correlated with the ancestral background around ApoE with the attenuated effect on African-originated haplotypes 15,16 .…”

IncreasedAPOEε4expression is associated with reactive A1 astrocytes and the difference in Alzheimer Disease risk from diverse ancestral backgrounds

“…However, the risk for AD conveyed by the APOEε4 allele varies between populations, with a stronger risk for APOEε4 homozygotes in Non-Hispanic Whites (NHW) (Odds Ratio (OR) ~15) [3][4][5][6] than for African-Americans (AA) (OR~8) and Africans (OR~3 for) [3][4][5][6][7][8][9] . Recent studies have shown the lower risk in African and AA APOEε4 carriers is associated with the African local genomic ancestry (LA) around the APOEε4 allele 10 . As there are no distinct amino acid changes in APOEε4 between AA and NHW, we hypothesized that noncoding variants affecting gene expression are likely involved.…”

“…To assess the LA, we phased our datasets (SHAPEIT version 229 ) using 1000 Genomes Phase 3 (1kGP) reference panel and used RFMix to infer LA at loci across the genome30 . We defined an initial region (chr19:44,000,000-46,000,000Mb) around the APOE locus that was broad enough to include potential enhancers, topological associated domains, and other regulatory factors while narrow enough to ensure contiguous LA blocks10 . After selecting the APOE LA region, we selected individuals homozygous for European (n=4) and African (n=4) local ancestry haplotypes.…”

Addition of Genetics to Quantitative MRI Facilitates Earlier Prediction of Dementia: A Non-invasive Alternative to Amyloid Measures

“…Although, the APOE e4 allele is a major risk factor for AD, odds ratios vary considerably among ethnic groups 42,43 , with the highest risk in East Asians 42,44 , followed by non-Hispanic Caucasians 42,45,46 and lowest in African ancestry populations 42,[47][48][49] . This may be the result of environmental factors, or population-specific genetic factors, with some evidence suggesting the latter 43 . Nonetheless, the odds-ratios derived from European studies of AD cannot be applied directly to non-European populations.…”