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Background: Alzheimer's disease (AD) and aging of the CNS are complex, heterogenous processes involving both structural and functional changes to neuronal and glial elements. While neuronal cell loss is well known, issues surrounding how age impacts both AD development and dementia and the metabolic and pathological changes that concomitantly occur are unclear. Major gaps in knowledge in aging of the CNS and AD involve changes in the excitatory/inhibitory balance between glutamate and GABA release and regulation with prior research supporting either elevated or reduced levels of resting glutamate. Method: Tonic and phasic glutamate release were measured in real time in vivo through the utilization of enzyme‐based microelectrode arrays (MEAs). Young adult male and female C57BL6 mice (5‐8 months old) were the wild‐type (WT) control group and were compared to male and female old APP/PS1 knock‐in mice (13‐24 months old) and age matched WT controls. Glutamate was recorded in the hippocampus, frontal cortex, and striatum. Following recordings of basal glutamate levels, DL‐threo‐beta‐hydroxyaspartate (TBOA), was locally injected (100 nl/ 50mg/ml) in the brain to study glutamate uptake. Result: There was a trend for basal glutamate levels to be increased in the hippocampus of both aged APP/PS1 and aged WT mice when compared to young WT animals with highest levels in the aged WT group. In both the frontal cortex and striatum, there was a trend for decreased basal glutamate levels in aged APP/PS1 and WT mice when compared to young WT animals with lowest levels seen in the aged WT group for both brain regions. Conclusion: There were differences in glutamate extracellular regulation seen within the hippocampus, frontal cortex, and striatum of all animal groups and ages. In addition, we see evidence for age‐related increases in glutamate within the hippocampus of the aged animal groups. These data support that glutamate regulation is not homogenous in the CNS and that aging of the CNS may result in the greatest effect on glutamate regulation in the CNS, rather than genes that are implicated in the etiology of AD such as the APP and PS1 genes. Support provided by NIH grants RF1AG070952 and 1P01AG078116. [ABSTRACT FROM AUTHOR]