Identifying the mediating role of brain atrophy on the relationship between DNA damage repair pathway and Alzheimer's disease: A Mendelian randomization analysis and mediation analysis

Background DNA damage and repair (DDR) and structural atrophies in different brain regions were recognized as critical factors in the onset of Alzheimer's disease (AD). Objective We utilized Mendelian randomization (MR) to examine the causal effects of the DDR-related molecular traits on AD and the potential mediating roles of different brain region volumes. Methods In primary analysis, we utilized public genome-wide association studies of AD and summary data from existing molecular traits datasets, including gene expression, DNA methylation, and protein levels quantitative trait loci (eQTL, mQTL, and pQTL) in both blood and brain to examine their causal associations by summary-data-based MR analysis and additional five two-sample MR methods. Subsequently, mediation analysis explored the potential mediate roles of 13 imaging-derived brain volume phenotypes in the associations between the DDR pathways and AD through a network MR design. Results We found that the volumes of the right thalamus proper and global cerebral white matter mediated the causal pathways from EGFR to AD and relatively weak mediation effects of the right lateral ventricle volume in the causal pathways involving CHRNE, DNTT, and AD. Conclusions We identified causal relationships among DDR pathways, specific brain region volumes, and AD. Monitoring the molecular traits of these DDR-related genes and developing targeted drugs may help detect and interrupt the early progression of AD.