Small-World Networks and Their Relationship With Hippocampal Glutamine/Glutamate Concentration in Healthy Adults With Varying Genetic Risk for Alzheimer's Disease

Background Apolipoprotein E e4 allele (ApoE4) is the most common gene polymorphism related to Alzheimer's disease (AD). Impaired synaptic dysfunction occurs in ApoE4 carriers before any clinical symptoms. It remains unknown whether ApoE4 status affects the hippocampal neuromodulation, which further influences brain network topology. Purpose To study the relationship of regional and global network properties by using graph theory analysis and glutamatergic (Glx) neuromodulation in the ApoE isoforms. Study Type Prospective. Subjects Eighty-four cognitively normal adults (26 ApoE4 and 58 non-ApoE4 carriers). Field Strength/Sequence Gradient-echo echo-planar and point resolved spectroscopy sequence at 3 T. Assessment Glx concentration in bilateral hippocampi were processed with jMRUI (4.0), and graph theory metrics (global: gamma, lambda, small-worldness in whole brain; regional: nodal clustering coefficient (C-i) and nodal characteristic path length (L-i)) in top 20% highly connected hubs of subgroups (low-risk: non-ApoE4; high-risk: APOE4) were calculated and compared. Statistical Tests Two-sample t test was used to compare metrics between subgroups. Correlations between regional properties and Glx by Pearson's partial correlation with false discovery rate correction. Results Significant differences (P < 0.05) in C-i between subgroups were found in hubs of left inferior frontal, bilateral inferior temporal, and bilateral precentral gyri, right parahippocampus, and bilateral precuneus. In addition, there was a significant correlation between Glx in the left hippocampus and C-i in inferior frontal gyrus (r = -0.537, P = 0.024), right inferior temporal (r = -0.478, P = 0.043), right parahippocampus (r = -0.629, P = 0.016), left precentral (r = -0.581, P = 0.022), right precentral (r = -0.651, P = 0.003), left precuneus (r = -0.545, P = 0.024), and right precuneus (r = -0.567, P = 0.022); and L-i in left precuneus (r = 0.575, P = 0.032) and right precuneus (r = 0.586, P = 0.032) in the high-risk group, but not in the low-risk group. Data Conclusion Our results suggested that healthy ApoE4 carriers exhibit poorer local interconnectivity. Moreover, the close relationship between glutamate and small-world network properties in ApoE4 carriers might reflect a compensatory response to the impaired network efficiency. Evidence Level 2 Technical Efficacy Stage 3

Automated summary

The ApoE4 allele is the most common gene polymorphism related to Alzheimer's disease, and it remains unclear whether ApoE4 status affects hippocampal neuromodulation and brain network topology. This study found that healthy ApoE4 carriers exhibit poorer local interconnectivity and a close relationship between glutamate and small-world network properties in these carriers may reflect a compensatory response to impaired network efficiency.