Mediation Analysis and Mixed-Effects Models for the Identification of Stage-specific Imaging Genetics Patterns in Alzheimer's Disease.

Abstract

Alzheimer's disease (AD) is one of the most common and severe forms of Senile Dementia. Genome-wide association studies (GWAS) have identified dozens of AD susceptible loci. To better understand potential mechanism-of-action for AD, quantitative brain imaging features have been studied as mediators linking genetic variants to AD outcomes. In this study, Mediation analysis, Chow test and Mixed-effects Models are used to investigate the biological pathways by which genetic variants affect both brain structures/functions and disease diagnosis. We analyzed the imaging and genetics data collected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project, including a Polygenic Hazard Score (PHS) and 13 imaging quantitative traits (QTs) extracted from the AV45 PET scans quantifying the amyloid deposition in different brain regions of subjects from four separate diagnostic groups. Mediation analysis assessed the mediating effects of image QTs between PHS and diagnosis, whereas Chow test and Linear Mixed-Effects models were used to characterize intra-group differences in the associations between genetic scores and imaging QTs for different disease stages. Results show that promising stage-specific imaging QTs that mediate the genetic effect of the studied PHS on disease status have been identified, providing novel insights into the predictive power of the PHS and the mediating power of amyloid imaging QTs with respect to multiple stages over the AD progression.