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Background: Apolipoprotein E ɛ4 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: γ, λ, 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., (© 2021 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC. on behalf of International Society for Magnetic Resonance in Medicine.)

The glutamatergic cycle is essential in modulating memory processing by the hippocampal circuitry. Our combined proton magnetic resonance spectroscopy ( 1 H-MRS) and task-based functional magnetic resonance imaging (fMRI) study (using face-name paired-associates encoding and retrieval task) of a cognitively normal cohort of 67 healthy adults (18 ApoE4 carriers and 49 non-ApoE4 carriers) found altered patterns of relationships between glutamatergic-modulated synaptic signalling and neuronal activity or functional hyperaemia in the ApoE4 isoforms. Our study highlighted the asymmetric left-right hippocampal glutamatergic system in modulating neuronal activities in ApoE4 carriers versus non-carriers. Such brain differentiation might be developmental cognitive advantages or compensatory due to impaired synaptic integrity and plasticity in ApoE4 carriers. As there was no difference in myoinositol levels measured by MRS between the ApoE4 and non-ApoE4 subgroups, the mechanism is unlikely to be a response to neuroinflammation., (© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)