Alzheimer's disease and related dementias are influenced by genetic and environmental risk factors. We investigated the relationship between contextual exposures and cognitive outcomes, independent of Show more
Alzheimer's disease and related dementias are influenced by genetic and environmental risk factors. We investigated the relationship between contextual exposures and cognitive outcomes, independent of and in interaction with polygenic risk. Using the Multi-Ethnic Study of Atherosclerosis (N = 5687), we assessed the associations of contextual determinants representing the social, chemical, and built environment with incident dementia and late-life cognition using proportional hazards regression and generalized estimating equation models, then evaluated their joint effects stratified by genetic risk via Bayesian kernel machine regression. Neighborhood disadvantage was associated with higher dementia risk and poorer cognitive scores after adjusting for genetic risk and other individual-level covariates. Joint analysis of all contextual determinants indicated that more deleterious mixtures of contextual determinants are associated with lower late-life cognition among apolipoprotein E ɛ4 non-carriers with intermediate polygenic risk. Contextual determinants are associated with dementia and late-life cognition after adjusting for age, sex, education, and genetic risk. Show less
The APOE-ε4/ε4 genotype is the strongest genetic risk factor for sporadic Alzheimer's disease, though the relative risk is diminished in individuals with African ancestry. Through analysis of phased A Show more
The APOE-ε4/ε4 genotype is the strongest genetic risk factor for sporadic Alzheimer's disease, though the relative risk is diminished in individuals with African ancestry. Through analysis of phased APOE alleles, we identify a 19 bp deletion approximately 1.1 kb distal to the APOE 3'UTR in a SPI1 microglial transcription factor binding site. The deletion is present in 60% of African American APOE-ε4 homozygotes and reduces Alzheimer's disease odds ratio relative to individuals without the deletion. The deletion also delays Alzheimer's disease onset in APOE-ε4/ε4 cases with local African ancestry at APOE. The All of Us dataset confirms reduced Alzheimer´s disease risk associated with the deletion and identifies additional variants between APOE and APOC1 that disentangle APOE-ε4 neurological and lipid-related phenotypes. Functional assays reveal that the 19 bp deletion abolishes SPI1 repression at this region. Collectively, these findings describe a protective allele at APOE in African Americans that mediates APOC1 expression, reducing relative Alzheimer´s disease risk. Show less