Genetic risk for trajectories of cognitive decline and progression to dementia among Mexican Americans and non-Hispanic whites

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PROJECT SUMMARY/ABSTRACT Cognitive function, such as perception, memory, attention, language, etc., varies among individuals in the population, and declines across the continuum from normal brain aging to dementia. Heritable factors play an important role in determining such variation. Large-scale population-based studies have been conducted to understand the contribution of genetic variation to cognitive function primarily in the populations of European ancestry. Hispanics make up the largest ethnic minority group in the US. Epidemiological data have shown that US Hispanics have a higher risk of cognitive impairment and dementia than non-Hispanic whites that cannot be fully explained by their diverse historical, cultural, or socio-economic factors, suggesting an ethnicity-specific role that heritable factors may play, which, however, is poorly understood. Leveraging the multi-ethnic Texas Alzheimer’s Research and Care Consortium research cohort with extensively collected longitudinal cognitive and genetic data, we aim to explore the effects of genetic variations on the trajectories of cognitive decline and progression to dementia in Mexican Americans and non-Hispanic whites. We anticipate that the genetic architecture of cognitive function is heterogeneous between the two ethnic groups. Specifically, in Aim 1, we will assess ethnicity-specific genetic association with global cognition, memory, and executive function at baseline and over time, and with progression to Alzheimer’s disease (AD) via genome-wide association analysis; we will then evaluate the ability of an individual’s genetic profile to predict the risk of cognitive impairment and dementia using the polygenic risk score approach in Hispanics. In Aim 2, we will explore possible underlying mechanisms of the genetic association with cognitive function, trajectories of cognitive decline, and progression to AD by incorporating a variety of functional annotation sources and multi-layered human molecular (omics) data via bioinformatics, network and systems approaches. In summary, Hispanics remain severely underrepresented in existing genetic studies, which is likely to further exacerbate existing health disparities by limiting clinical applications of genetic research, such as risk prediction and tailored interventions. Our exploratory effort will lay the foundation for future larger and more comprehensive investigations, which may have the potential to guide AD risk prediction, to enhance detection of asymptomatic individuals with preclinical AD, to optimize clinical trial design, and to foster targeted interventions in high-risk subgroups. Further coupling the findings with multi-omics data will help uncover the underlying molecular pathways of the observed genetic association, which may ultimately lead to novel therapeutic target discoveries.