Alzheimer's disease polygenic scores and cognition

Our goal is to investigate the roles of cumulative genetic variation, disparity-related factors, and their interactions on late-onset Alzheimer’s disease (LOAD) and dementia phenotypes, extending precision public health to environmental susceptibility across ancestries. LOAD is the leading terminal form of dementia affecting a growing number of aging U.S. adults. As LOAD risk is disproportionately high among minorities, women, rural inhabitants, and people with lower education, disparities in LOAD risk represent a critical knowledge gap. Novel approaches characterizing the multifaceted etiology of LOAD disparities are needed to identify the genetic underpinnings, biological pathways, and potentially modifiable environmental factors that lead to sustained LOAD disparities.
We propose whole genome estimations of polygenic risk of cognition, LOAD, and LOAD risk factors to be examined for their effect on dementia phenotypes among individuals >70, independently and in concert; potential interactions between PGS and factors with disparities in LOAD; and application of our methods in European and African ancestry groups (Fig. 1).
AIM 1. Determine the cumulative genetic risk of LOAD by estimating the effect of cognitive polygenic scores on dementia phenotypes in individuals of European and African ancestry.
AIM 2. Determine the association between polygenic scores for a) behavioral, b) physiological, and c) social/psychosocial domains and dementia phenotypes in individuals of European and African ancestry. We will consider Mendelian Randomization approaches for this aim.
AIM 3. For the relationships between polygenic scores and dementia phenotypes (AIMS 1 and 2), test for effect modification by LOAD disparity-related factors (sex, educational attainment, urban/rural), in individuals of European and African ancestry.
We area also exploring stratification by the APOE risk variants.

The overall purpose of this proposal is to establish the relevance of polygenic risk in susceptibility to dementia, particularly among groups at increased risk of disease, including women, minorities, rural inhabitants, and those with low educational attainment. Because an individual’s susceptibility to dementia is likely a combination of genetics and environmental risk factors, we will jointly test the effects of cumulative genetic risk and dementia risk factors in our analysis. The proposal provides an opportunity to identify a genetic etiologic component in vulnerable groups that could lead to mechanistic understanding or targeted interventions to substantially benefit public health in the US.