Multivariate mediation analysis with voxel-based morphometry revealed the neurodegeneration pathways from genetic variants to Alzheimer's Disease.

Neurodegenerative processes are increasingly recognized as potential causative factors in Alzheimer's disease (AD) pathogenesis. While many studies have leveraged mediation analysis models to elucidate the underlying mechanisms linking genetic variants to AD diagnostic outcomes, the majority have predominantly focused on regional brain measure as a mediator, thereby compromising the granularity of the imaging data. In our investigation, using the imaging genetics data from a landmark AD cohort, we contrasted both region-based and voxel-based brain measurements as imaging endophenotypes, and examined their roles in mediating genetic effects on AD outcomes. Our findings underscored that using voxel-based morphometry offers enhanced statistical power. Moreover, we delineated specific mediation pathways between SNP, brain volume, and AD outcomes, shedding light on the intricate relationship among these variables.