Glutamatergic and GABAergic metabolite levels in Alzheimer’s disease: a systematic review and meta-analysis

This systematic review and meta-analysis compares glutamate, glutamine, and GABA levels in cerebrospinal fluid (CSF), blood, and brain tissue between individuals with Alzheimer's disease (AD) and cognitively unimpaired (CU) controls. We systematically searched PubMed and Web of Science up to February 20, 2025, for studies reporting GABA, glutamate, or glutamine levels in AD and CU controls. Effect sizes were calculated using Hedges' g, with heterogeneity assessed via I² statistics and publication bias evaluated using funnel plots and Egger's and Begg's tests. From 14,857 records, 53 studies were included. Glutamate levels were significantly lower in AD brains, including the cortex (SMD = - 0.42; 95% CI [-0.79, - 0.05]; I² = 67.26%; p = 0.03), hippocampus (SMD = - 0.56; 95% CI [-0.91, - 0.20]; I² = 37.29%; p < 0.05), and temporal cortex (SMD = - 0.87; 95% CI [-1.52, - 0.23]; I² = 77.60%; p = 0.01), but not in CSF or blood. Glutamine showed no significant differences in brain regions, CSF, or blood. GABA levels were significantly lower in AD patients across the cortex (SMD = - 0.53; 95% CI [-0.81, - 0.25]; I² = 58.60%; p < 0.05), CSF (SMD = - 0.38; 95% CI [-0.65, - 0.11]; I² = 0.00%; p = 0.01), and blood (SMD = - 0.72; 95% CI [-1.08, - 0.37]; I² = 43.18%; p < 0.05). Our findings underscore the potential of targeting glutamatergic and GABAergic systems in AD clinical research. We recommend prioritizing future investigations in earlier disease stages, such as preclinical AD and mild cognitive impairment.