African Haplotypic Background Mitigates the Effect of APOE e4 Risk Allele in Alzheimer Disease (P2.195)

Objective: Our objective is to evaluate the role of race/ethnicity and genetic ancestry at APOE gene in African American (AA) and Caribbean Hispanic (CHI) populations. Background: Alzheimer disease (AD) is a progressive neurodegenerative disease and occurs in all ethnic and racial groups. The APOE gene’s ɛ4 allele ( ApoE4 ) is a major risk factor for AD whose effect shows strong racial/ethnic differences. The underlying reasons for differential ApoE4 effects across the populations are not clear. The differences may be due to the ancestry-specific genetic factors or due to environmental/cultural factors. One way to explore these is using local ancestry (LA) methods. LA refers to the ancestral background of a particular chromosomal region and may be correlated with ancestry-specific genetic factors that are located in or near the genomic region in question. Thus, our goal to assess the relevance of the LA to the differential effect of the ApoE4 in AA and CHI. Design/Methods: ApoE4 and genome-wide genotyping were performed in 2,229 AA (811 cases, 1,418 controls) and 267 Puerto Rican (PR) CHI samples (169 cases, 98 controls). LA was calculated using SHAPEIT and RFMix. Association between affection status and ApoE4 genotype in the presence of the LA was analyzed using genotype-based and haplotype-based logistic regression models. Results: The genotype-based models showed that ApoE xLA interaction term significantly associated with AD in the PR (p=0.048) and AA (p=0.008). The haplotype-based model showed that PR and AA individuals with European LA (PR:OR=4.18(1.79–9.78); AA:OR=2.83(1.99–4.02)) have a stronger ApoE4 effect than those with AF LA(PR:OR=2.54(0.59–10.98); AA:OR=2.18(1.85–2.58)). Conclusions: Given the discordance between the previous racial disparities in ApoE4 risk, we showed that the LA at APOE has a larger effect rather than environmental or ethnic interaction. This highly suggests that the APOE region from AF populations may harbor protective factors that help mitigate the effect of the ApoE4 . Study Supported by: This investigation was supported by grant “Genomic Characterization of Alzheimer’s Disease Risk in the Puerto Rican Population” (1RF1AG054074), and “Alzheimer’s Disease Genetics Consortium”, (U01AG032984) from the National Institutes on Aging of NIH. Disclosure: Dr. Rajabli has nothing to disclose. Dr. Feliciano-Astacio has nothing to disclose. Dr. Celis has nothing to disclose. Dr. Hamilton has nothing to disclose. Dr. Whitehead has nothing to disclose. Dr. Adams has nothing to disclose. Dr. Bussies has nothing to disclose. Dr. McCauley has nothing to disclose. Dr. Acosta has nothing to disclose. Dr. Chinea has nothing to disclose. Dr. Betancourt has nothing to disclose. Dr. Byrd has nothing to disclose. Dr. Martin has nothing to disclose. Dr. Reitz has nothing to disclose. Dr. Farrer has nothing to disclose. Dr. Schellenberg has nothing to disclose. Dr. Mayeux has nothing to disclose. Dr Vance has nothing to disclose. Dr. Cuccaro has nothing to disclose. Dr. Haines has nothing to disclose. Dr. Vardarajan has nothing to disclose. Dr. Beecham has nothing to disclose. Dr. Pericak-Vance has nothing to disclose.