Socio-Contextual and Multi-Omic Associations with Cognitive Function and Structural Brain Measures in Older African Americans

Abstract

Dementia affects approximately 1 in 10 persons aged 65 years and older in the U.S., and African Americans (AA) are more likely to develop dementia compared to European Americans (EA). However, the underlying molecular mechanisms and impact of their interactions with socio-contextual risk factors on cognitive function and brain structures in AA are not fully understood. This dissertation examines the molecular effects of genetic, epigenetic, and transcriptomic markers, as well as socio-contextual determinants of health, on cognitive function and white matter hyperintensity (WMH) prior to dementia onset in a well-curated cohort of older AA from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. In Aim 1, we investigated whether single nucleotide polymorphisms (SNPs), epigenetic variants, and/or their interactions in the ABCA7 gene region, which was previously associated with Alzheimer’s Disease (AD) in AA, are associated with general cognitive function in cognitively normal older AA. Although ABCA7 sentinel SNPs and CpG sites were not associated with general cognitive function, we did see evidence of SNP-by-CpG interactions. We found that rs3764647 and rs115550680 may regulate the effects of DNA methylation (DNAm) on cognitive function. As such, while AD risk SNPs in ABCA7 were not associated with cognitive function in this sample, DNAm at local CpGs may influence cognitive function in people with specific ABCA7 genotypes. In Aim 2, we assessed whether DNAm from peripheral blood leucocytes mediates the relationships between neighborhood characteristics and cognitive function/WMH in cognitively healthy AA, using high-dimensional mediation methods. For a 1-mile buffer around a participant’s residence, each additional fast-food destination or unfavorable food store with alcohol per square mile was associated with 0.05 (p=0.04) and 0.04 (p=0.04) second improvements in visual conceptual tracking score, respectively. Also, each additional alcohol drinking place per square mile was associated with a 0.62 word increase in delayed recall score (p=0.03), indicating better memory function. Although the presence of these destinations encourages unhealthy diet and behaviors, they may provide meeting places for community members that allow for greater interaction and stimulation of cognitive health. In this study, there was no evidence that DNAm mediated the observed associations between neighborhood characteristics and cognitive function. Further examination of the pathways between neighborhood characteristics and cognitive function/WMH may allow for development of behavioral, infrastructural, and pharmaceutical interventions to facilitate healthy brain aging in older AA. In Aim 3, we conducted a multi-ancestry transcriptome wide association study (TWAS) that leveraged gene expression data collected from EA and AA in GENOA, through a joint likelihood-based inference framework, to identify genes associated with general cognitive function, WMH, and AD. After fine-mapping within genomic regions, we identified 266, 23, and 69 genes associated with general cognitive function, WMH, and AD, respectively (Bonferroni-corrected alpha level =P<2.9x10-6). These genes were enriched for innate immunity, vascular dysfunction, and neuroinflammation. The WMH and AD TWAS also indicated that downregulation of ICA1L may contribute to overlapping AD and vascular dementia (VaD) neuropathology. To our knowledge, this study is the first TWAS of cognitive function and neurocognitive disorders that used expression mapping studies in multiple ancestries. This work may expand TWAS studies beyond a single ancestry group to identify gene targets for pharmaceutical or preventative treatment for dementia. Together, these studies advance knowledge of the relationships between multi-omic mechanisms and socio-contextual factors that contribute to neurocognitive outcomes and structural brain measures in older AA.