Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. ApoE ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic White populations and has a relatively lower effect in African descent populations. Admixture analysis in the African American and Puerto Rican populations showed that the variation in ε4 risk is correlated with the genetic ancestral background local to the ApoE gene. Native American populations are substantially underrepresented in AD genetic studies. The Peruvian population with up to ∼80 of Amerindian ancestry provides a unique opportunity to assess the role of Amerindian ancestry in Alzheimer disease. In this study we assess the effect of the ApoE ε4 allele on AD in the Peruvian population.A total of 78 AD cases and 128 unrelated cognitive healthy controls were included in the study. Genome-wide genotyping was performed using the Illumina Global screening array. Global ancestry and local ancestry analyses were assessed. The effect of the ApoE ε4 allele on Alzheimer disease was tested using a logistic regression model by adjusting for age, gender, and population substructure (first three principal components). Logistic regression results showed that ApoE ε4 allele is significantly associated with AD in Peruvian population with the high-risk effect (OR = 5.02, CI: 2.3-12.5, p-value = 2e-4). The average values of the local ancestries surrounding the ApoE gene (chr19:44Mb-46Mb) have the highest proportion of Amerindian (60.6%), followed by European (33.9%) and African (5.5%) ancestral backgrounds.Our results showed that the risk for AD from ApoE ε4 in Peruvians is higher than we have observed in non-Hispanic White populations. Given the high admixture of Amerindian ancestry in the Peruvian population, it suggests that the Amerindian local ancestry is contributing to a strong risk for AD in ApoE ε4 carriers. Our data also support the findings of an interaction between the genetic risk allele ApoE ε4 and the ancestral backgrounds located around the genomic region of ApoE gene.