GABAergic system in Alzheimer’s disease: a systematic review with meta‐analysis
Bibliographic record
Abstract
Abstract Background Cholinergic and glutamatergic dysfunctions have been widely described in Alzheimer’s disease (AD). However, the role of other neurotransmitter systems, such as the GABAergic, remains poorly understood. In fact, studies evaluating GABAergic neurotransmission in AD patients have provided contradictory results, pointing to a need for a consensus in the literature regarding the GABAergic system in AD. Thus, we aimed at examining whether the GABAergic system is altered in AD. Method We systematically reviewed and meta‐analyzed the literature following the PRISMA 2020 guidelines (PROSPERO #alz064082). We searched in the PubMed and Web of Science databases for studies reporting quantitative or semi‐quantitative data of GABA, and GABAergic transporters, receptors, and synthesis enzymes. The participants included were AD subjects and age‐matched cognitively unimpaired (CU) individuals. The effect sizes were determined via the standardized mean difference (SMD) using Hedge’s g method with random effects. The percentage of heterogeneity between studies was estimated using I2 test. Data are presented as SMD [95% CI], I2 %. Result The search identified 3,223 papers (Figure 1). Forty‐nine records met the inclusion criteria (a total of 667 AD patients, mean age 75.4, and 584 CU subjects, mean age 72.4). Here, we present results obtained in the CSF, blood, and different brain regions in which more than five studies have been meta‐analyzed. GABA levels were decreased in the CSF (‐0.42 [‐0.74, ‐0.1], p<0.0001, 0%), temporal cortex (‐0.97 [‐1.38, ‐0.55], p<0.0001, 54.6%), occipital cortex (‐1.03 [‐1.86, ‐0.2], p=0.015, 78%), and striatum (‐0.58 [‐1.09, ‐0.07], p=0.025, 0%), but not in the blood (‐0.64 [‐1.39, 0.11], p=0.092, 64.2%), frontal cortex (‐0.49 [‐1.06, 0.08], p=0.09, 73.1%), and hippocampus (‐0.39 [‐0.8, 0.03], p=0.068, 24.7%); GABA A receptor availability was decreased in the frontal (‐0.74 [‐1.44, ‐0.05], p=0.037, 50.5%) and temporal cortices (‐0.73 [‐1.15, ‐0.3], p=0.001, 7.4%), but not in the hippocampus (‐0.79 [‐1.64, 0.06], p=0.068, 66.9%). Figure 2 provides a summary of our findings. Conclusion Our results demonstrated a decrease of GABAergic system components in multiple brain regions and low levels of GABA in the CSF of AD subjects compared to age‐matched CU individuals, pointing to an important role played by GABAergic neurotransmission in the pathophysiology of 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 | 0.011 | 0.023 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.018 | 0.032 |
| Bibliometrics | 0.007 | 0.009 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.001 |
| 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".