The Glutamatergic System in Alzheimer’s Disease: A Systematic Review with Meta‐analysis
Bibliographic record
Abstract
Abstract Background Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer’s disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta‐analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. Method We searched PubMed and Web of Science(database origin‐October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D‐serine, metabotropic and ionotropic glutamate receptors in the AD human brain. The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain(cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2statistics. Result The search retrieved 6 936 articles,63 meeting the inclusion criteria(N = 709CN/786AD;mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = ‐0.82;P<0.001) and aspartate levels (SMD = ‐0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = ‐0.75;P<0.001). We also found reduced AMPAR‐GluA2/3 levels(SMD = ‐0.63;P = 0.046), hypofunctional NMDAR (SMD = ‐0.60;P<0.001) and selective reduction of NMDAR‐GluN2B subunit levels(SMD = ‐1.07;P<0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR‐GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR‐GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Conclusion Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate‐mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.014 | 0.033 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.019 | 0.030 |
| Bibliometrics | 0.007 | 0.010 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".