Biological characterization of multimodal imaging-derived phenotypes through Alzheimer’s disease polygenic pathways.

COEX 

Little is known about the genetic factors and the downstream molecular pathways determining individual variability in MRI-derived endophenotypes. Unraveling how genetic variability is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, are key steps towards precision medicine for several polygenic diseases, such as Alzheimer’s disease (AD). This talk will demonstrate the use of pathways and functional enrichment analysis to biologically characterize multimodal imaging-derived metrics. We studied AD polygenic risk score and performed functional enrichment analysis to measure genetic risk related to specific biological pathways, such as neuroinflammation, immune activation and amyloid clearance. We further used pathway-specific PRS to biologically characterize multimodal imaging biomarkers including gray matter volumes, white matter hyperintensities (WMH) volumes, fractional anisotropy from diffusion tensor imaging, and resting-state network functional connectivity. This study reveals distinct genetic risk-profiles in association with specific AD pathophysiological aspects, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes.