Global and local ancestry modulate APOE association with Alzheimer's neuropathology and cognitive outcomes in an admixed sample

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 of APOE epsilon 4 risk of dementia in African ancestry (AFR), but a dearth of neuropathological data preclude the interpretation of the biological factors underlying these findings, including the association between APOE epsilon 4 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 a severe burden of NP and neurofibrillary tangles (NFT), AFR proportion was associated with worse Clinical Dementia Rating sum of boxes (CDR-SOB). Among APOE epsilon 4 carriers, the association between AFR proportion and CDR-SOB disappeared. APOE local ancestry inference of a subset of 309 individuals revealed that, in APOE epsilon 4 noncarriers, non-European APOE background correlated with lower NP burden and, also, worse cognitive outcomes than European APOE when adjusting by NP burden. Finally, APOE epsilon 4 was associated with worse AD neuropathological burden only in a European APOE background. APOE genotype and its association with AD neuropathology and clinical pattern are highly influenced by ancestry, with AFR associated with lower NP burden and attenuated APOE epsilon 4 risk compared to European ancestry.

Automated summary

Dementia is more common in Blacks than in Whites, possibly due to a combination of environmental and biological factors. Interestingly, studies have shown a lower risk of dementia associated with APOE epsilon 4 in individuals of African ancestry. However, the underlying biological factors are not well understood. This study found that African ancestry was associated with a lower burden of neuropathology, but in individuals with severe neuropathology, it was associated with worse clinical symptoms of dementia.