Dementia is more prevalent in Blacks than in Whites, likely due to a combination of environmental and biological factors. Paradoxically, clinical studies suggest an attenuation ofAPOEε4 risk of dementia in African ancestry (AFR), but lack of neuropathological data preclude the interpretation of the biological factors underlying these findings, including the association betweenAPOEε4 risk and Alzheimer’s disease (AD) pathology, the most frequent cause of dementia. We investigated the interaction between African ancestry, AD-related neuropathology,APOE genotype, and functional cognition in a postmortem sample of 400 individuals with a range of AD pathology severity and lack of comorbid neuropathology from a cohort of community-dwelling, admixed Brazilians. Increasing proportions of African ancestry (AFR) correlated with a lower burden of neuritic plaques (NP). However, for individuals with high levels of NP and neurofibrillary tangles (NFT), AFR proportion was associated with worse Clinical Dementia Rating sum of boxes (CDR-SOB). AmongAPOEε4 carriers, the association between AFR proportion and CDR-SOB disappeared.APOElocal ancestry inference of a subset of 309 individuals revealed that, inAPOEε4 noncarriers, non-EuropeanAPOEbackground associated with lower NP burden, but with worst cognitive outcomes compared to EuropeanAPOEwhen adjusting by the similar NP burden. Finally,APOEε4 was associated with worse AD neuropathological burden only in a EuropeanAPOEbackground.APOEgenotype and its association with AD neuropathology and clinical pattern are highly influenced by ancestry, with AFR associated with lower NP burden and attenuatedAPOE4risk compared to European ancestry.