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

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 < .001), the calculation score (F3, 87 = 6.218; p = .015), and the volume in prefrontal (F3, 87 = 4.374; p = .039) and orbitofrontal cortices (F3, 87 = 6.022; p = .016). The calculation score was correlated with each frontal volume (cc) (rho = 0.304; p = .004) and genetic interaction-associated FC in ECN (rho = 0.282; p = .008). Variations in genotypes affected the relationship between the calculation score and each frontal volume (cc). 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.