APOE-MS4A genetic interactions are associated with executive dysfunction and network abnormality in clinically mild Alzheimer's disease

Abstract Purpose of the research Although single nucleotide polymorphisms of membrane-spanning 4A ( MS4A ) (rs670139) and several other susceptibility genes have shown interaction effects on the risk of Alzheimer's disease (AD), little is known about the interaction effects of apolipoprotein E ( APOE ) with MS4A (rs670139) on cognitive performances, and the underlying pathogenesis is unclear. The study aimed to investigate the APOE - MS4A (rs670139) interaction effects on cognitive performances, cortical volumes, and functional connectivity (FC) in brain networks. Principal results Cognitive performances were characterized in each genotypic group, and were compared between normal controls and patients in each genotypic group. APOE - MS4A interaction effects on memory and executive function scores, cortical volumes, and FC in brain networks were demonstrated. Significant effects of APOE - MS4A interactions on FC were observed in executive control network (ECN) (T maxima = 4.99, false discovery rate-corrected p  Major conclusions These findings indicate that the genetic interaction effects on FC in ECN might contribute to pathogenic mechanisms underlying the interaction effects of APOE - MS4A on calculation ability in AD.