THE GLUTAMATERGIC SYSTEM IN ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW WITH META‐ANALYSIS

Abstract Background Glutamate is the most important excitatory neurotransmitter in the human brain, and the regulation of its homeostasis is of utmost importance for brain proper functioning. At the synapse level, glutamate binds to ionotropic (NMDAR, AMPAR and KAR) and metabotropic receptors (8 isoforms, mGluR1 to mGluR8). Also located at the glutamatergic synapse are the vesicular transporters (vGLUT), a synaptic marker, and glutamate transporters (GLT1), which are responsible for glutamate re‐uptake. Increases in the glutamate concentration in the synaptic cleft leads to a phenomenon called excitotoxicity, which causes progressive neuronal death. Nonetheless, glutamate excitotoxicity has been described as a common feature in neurodegenerative disorders, including Alzheimer’s Disease (AD). Multiple studies reported alterations in the glutamatergic system in the AD brain. Thus, considering the large number of publications, we sought to perform a systematic review with meta‐analysis to assess whether the glutamatergic system is consistently altered in AD patients. Method PubMed and Web of Science databases were searched for articles that evaluated glutamatergic system components in AD. Pooled effect sizes were determined with standardized mean differences using the Hedge G method with random effects. Result The search initially retrieved 6000 articles. Following exclusion criteria, 59 articles were included in this study. We found that regions typically affected with AD pathology presented reduced NMDAR subunit NR1 (p = 0.017, z = 2.38, i 2 = 71.3%) (Figure 1), NR2A (p = 0.001, z = 3.38, i 2 = 0%) (Figure 2), NR2B (p < 0.0001, z = 3.86, i 2 = 0%) (Figure 3), AMPAR subunits GluA2/3 (p = 0.018, z = 2.36, i 2 = 84.5%) (Figure 4). Conversely, we did not observe significant differences in the level of GLT1, vGLUT1, vGLUT2, AMPAR subunit GluA1 and mGluRs in postmortem brain tissue. Further analyses are in process to assess other glutamatergic components, as well sensitivity analysis considering risk of bias for each study. Conclusion In conclusion, the early results of this meta‐analysis suggest that changes in the glutamatergic system in AD are not generalized, but specifically related to ionotropic receptors.