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APOE-MS4A genetic interactions are associated with executive dysfunction and network abnormality in clinically mild
Ya-Ting Chang1, Etsuro Mori2, Maki Suzuki2
1Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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) (ρ = 0.304; p = .004) and genetic interaction-associated FC in ECN (ρ = 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.
Insights
The interaction of apolipoprotein E (APOE) and membrane-spanning 4A (MS4A) genetic variations impacts brain functional connectivity and cognitive performance, potentially revealing new pathways in Alzheimer's disease pathogenesis.
Area of Science:
- Neurogenetics
- Alzheimer's Disease Research
- Cognitive Neuroscience
Background:
- Genetic factors like single nucleotide polymorphisms (SNPs) in MS4A and APOE influence Alzheimer's disease (AD) risk.
- The specific interaction effects of APOE and MS4A (rs670139) on cognitive functions and their underlying biological mechanisms remain largely unexplored.
Purpose of the Study:
- To investigate the interaction effects of apolipoprotein E (APOE) and membrane-spanning 4A (MS4A) (rs670139) on cognitive performance.
- To examine how this genetic interaction influences cortical volumes and functional connectivity (FC) within brain networks.
- To elucidate the potential pathogenic mechanisms linking APOE-MS4A interactions to cognitive function in AD.
Main Methods:
- Cognitive performances were assessed across different genotypic groups.
- Comparisons were made between normal controls and AD patients within each genotypic group.
- Brain imaging techniques were used to analyze cortical volumes and functional connectivity (FC) in relation to APOE-MS4A genotypes.
Main Results:
- Significant APOE-MS4A interaction effects were observed on functional connectivity (FC) in the executive control network (ECN).
- The interaction also affected calculation scores and the volumes of prefrontal and orbitofrontal cortices.
- The calculation score showed correlations with frontal lobe volumes and ECN functional connectivity, with genotype variations influencing these relationships.
Conclusions:
- Genetic interactions between APOE and MS4A significantly influence brain functional connectivity, particularly in the ECN.
- These interactions are associated with alterations in specific cognitive abilities, such as calculation, and brain structure.
- The findings suggest that APOE-MS4A genetic interactions contribute to the pathogenesis of cognitive deficits observed in Alzheimer's disease.