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

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Naslavsky, Michel Satya ; Suemoto, Claudia K. ; Brito, Luciano Abreu ; Scliar, Marilia Oliveira ; Ferretti-Rebustini, Renata Eloah ; Rodriguez, Roberta Diehl ; Leite, Renata E. P. ; Araujo, Nathalia Matta ; Borda, Victor ; Tarazona-Santos, Eduardo ; Jacob-Filho, Wilson ; Pasqualucci, Carlos ; Nitrini, Ricardo ; Yaffe, Kristine ; Zatz, Mayana ; Grinberg, Lea T.

• Document type: Journal article
• Source: MOLECULAR PSYCHIATRY; v. 27, n. 11, p. 9-pg., 2022-09-07.

Abstract

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. (AU)

• FAPESP's process: 16/24326-0 - Characterization of tau astrogliopathy on aging and neurodegenerative diseases
• Grantee: Roberta Diehl Rodriguez
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 06/55318-1 - Nosological diagnosis of dementia in a Brazilian population
• Grantee: Ricardo Nitrini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/16626-0 - Study of causes of mortality among the different forms of dementia in data series from community sample submitted to autopsy and anatomic pathological analysis
• Grantee: Beatriz Astolfi Neves
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 14/50931-3 - Aging and genetic disorders: genomics and metagenomics
• Grantee: Mayana Zatz
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 09/09134-4 - The cognitive reserve in a population with low educational attainment
• Grantee: Wilson Jacob Filho
• Support Opportunities: Regular Research Grants