Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans

Article type: Research Article

Authors: Mezlini, Aziz M.^{a; b} | Magdamo, Colin^a | Merrill, Emily^a | Chibnik, Lori B.^{a; b; c} | Blacker, Deborah L.^{c; d} | Hyman, Bradley T.^{a; b} | Das, Sudeshna^{a; b; *}

Affiliations: [a] MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA | [b] Department of Neurology, Harvard Medical School, Boston, MA, USA | [c] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA | [d] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Sudeshna Das, 65 Landsdowne Street, Cambridge, MA, USA. Tel.: +1 617 768 8254; E-mail: [email protected].

Abstract: Background:The APOE ɛ4 allele is the largest genetic risk factor for late-onset Alzheimer’s disease (AD). Recent literature suggested that the contribution of APOE ɛ4 to AD risk could be population-specific, with ɛ4 conferring a lower risk to Blacks or African Americans. Objective:To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA). Methods:We selected data from 1) the National Alzheimer’s Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes from the Alzheimer’s Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU. Results:In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOE ɛ4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification. Conclusion:Our study finds similar effects of the ɛ4-linked haplotypes defined by rs769449 on AD as compared to ɛ3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations.

Keywords: African Americans, APOE , clinicopathological features, Europeans, genotype

DOI: 10.3233/JAD-200228

Journal: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 467-477, 2020