Global and local ancestry modulateAPOEassociation with Alzheimer’s neuropathology and cognitive outcomes in an admixed sample

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 ϵ4 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 between APOE ϵ4 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). Among APOE ϵ4 carriers, the association between AFR proportion and CDR-SOB disappeared. APOE local ancestry inference of a subset of 309 individuals revealed that, in APOE ϵ4 noncarriers, non-European APOE background associated with lower NP burden, but with worst cognitive outcomes compared to European APOE when adjusting by the similar NP burden. Finally, APOE ϵ4 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 ϵ4 risk compared to European ancestry.

Causal effects on complex traits are similar across segments of different continental ancestries within admixed individuals

“…Unfortunately admixed populations are vastly under-represented in genomic studies 18 , partly because of the lack of understanding of how the genetic causal effects vary across ancestries 13,17,17,[19][20][21][22] . For example, heterogeneity of marginal effects for a few traits and loci has been reported [23][24][25][26] , however it remains unknown whether this reflects true difference in genetic effects or confounding due to different allele frequencies and/or linkage disequilibrium (LD) by ancestry. Recent works 15 have reported evidence of causal effect heterogeneity for SNPs in regions of European ancestries shared across European American and admixed African American individuals; however, they did not compare effects difference across ancestries within admixed populations.…”

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

“…It is well known, for instance, that the APOE risk effects on AD are ancestry-dependent. 57,58 Fourth, it is important to emphasize, that our mediation analyses are based on the assumption that the analyzed CSF biomarkers reflect pathological processes that precede and cause AD symptoms. An alternative – and often times equally plausible – interpretation is that the uncovered SNPs affect AD symptoms independently of biomarker levels and that the component associations observed here actually reflect a consequence of AD pathogenesis.…”

Air Pollution Exposure During Pregnancy and Childhood, Apoe Ε4 Status and Alzheimer Polygenic Risk Score, and Brain Structural Morphology in Preadolescents

“…In our study, we included mothers with a singleton pregnancy whose children had available genotype data and a European ethnic origin (N = 2796). Using a European population improves the performance of the PRS and allows for correct assessment of the APOE genotype with neurodevelopmental burden, since this is dependent on ancestry (Baker and Escott-Price, 2020;Naslavsky et al, 2022). When children were between 9 and 12 years old, those still involved in the study were invited to participate in a magnetic resonance imaging (MRI) scanning session (White et al, 2018).…”