Abstract Changes in levels of the inhibitory neurotransmitter γ‐aminobutyric acid (GABA) may underlie aging‐related changes in brain function. GABA and co‐edited macromolecules (GABA+) can be measured with MEGA‐PRESS magnetic resonance spectroscopy (MRS). The current study investigated how changes in the aging brain impact the interpretation of GABA+ measures in bilateral auditory cortices of healthy young and older adults. Structural changes during aging appeared as decreasing proportion of grey matter in the MRS volume of interest and corresponding increase in cerebrospinal fluid. GABA+ referenced to H2O without tissue correction declined in aging. This decline persisted after correcting for tissue differences in MR‐visible H2O and relaxation times but vanished after considering the different abundance of GABA+ in grey and white matter. However, GABA+ referenced to creatine and N‐acetyl aspartate (NAA), which showed no dependence on tissue composition, decreased in aging. All GABA+ measures showed hemispheric asymmetry in young but not older adults. The study also considered aging‐related effects on tissue segmentation and the impact of co‐edited macromolecules. Tissue segmentation differed significantly between commonly used algorithms, but aging‐related effects on tissue‐corrected GABA+ were consistent across methods. Auditory cortex macromolecule concentration did not change with age, indicating that a decline in GABA caused the decrease in the compound GABA+ measure. Most likely, the macromolecule contribution to GABA+ leads to underestimating an aging‐related decrease in GABA. Overall, considering multiple GABA+ measures using different reference signals strengthened the support for an aging‐related decline in auditory cortex GABA levels.
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