The GABAergic system in Alzheimer’s disease: a systematic review with meta-analysis
Abstract
The γ-aminobutyric acid (GABA)ergic system is the primary inhibitory neurotransmission system in the mammalian brain. Its dysregulation has been shown in multiple brain conditions, but in Alzheimer's disease (AD) studies have provided contradictory results. Here, we conducted a systematic review with meta-analysis to investigate whether the GABAergic system is altered in AD patients compared to healthy controls (HC), following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 18 th , 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABA A , GABA B, and GABA C receptors, GABA transporters (GAT) 1-3 and vesicular GAT in the brain, and GABA levels in the cerebrospinal fluid (CSF) and blood. Heterogeneity was estimated using the I 2 index, and the risk of bias was assessed with an adapted questionnaire from the Joanna Briggs Institute Critical Appraisal Tools. The search identified 3631 articles, and 48 met the final inclusion criteria (518 HC, mean age 72.2, and 603 AD patients, mean age 75.6). Random-effects meta-analysis [standardized mean difference (SMD)] revealed that AD patients presented lower GABA levels in the brain (SMD = -0.48 [95% CI = -0.7, -0.27], adjusted p value (adj. p) A receptor (-0.51 [-0.7, -0.33], adj. p < 0.001), and GABA transporters (-0.51 [-0.92, -0.09], adj. p = 0.016) were lower in the AD brain. Here, we showed a global reduction of GABAergic system components in the brain and lower…
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Interplay between excitatory and inhibitory neurotransmitter systems, particularly dysregulation of GABA, may further tip balance toward hyperexcitability and network dysfunction in AD.
“Moreover, the interplay between excitatory and inhibitory neurotransmitter systems, particularly the dysregulation of γ-aminobutyric acid (GABA), may further tip the balance toward hyperexcitability and network dysfunction in AD [121].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [121]
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- Authors
- Carello-Collar, G., Bellaver, B., Ferreira, P. C. L., Ferrari-Souza, J. P., Ramos, V. G., Therriault, J., Tissot, C., De Bastiani, M. A., Soares, C., Pascoal, T. A., Rosa-Neto, P., Souza, D. O., & Zimmer, E. R.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- McGill University Research Centre for Studies in Aging (CA)
- University of Pittsburgh (US)
- Corresponding author
- Zimmer, Eduardo R.
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2023-07-07
- Volume
- 28
- Issue
- 12
- Pages
- 5025-5036
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W4383534628
- Cited by
- 98
- References
- 12
- Citations by year
- 2026: 33 · 2025: 43 · 2024: 17 · 2023: 5
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (NIRP-12-259245, AARF-D-22-923814, AARGD-21-850670, AARFD-22-974627, #NIRG‐12‐92090, AACSF-20-648075)
- Canadian Institutes of Health Research
- National Institute on Aging (R01AG073267, R01AG075336)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, GABAergic system, GABA levels, GAD65/67, GABAA receptor, GABAB receptors, GABAC receptors, GABA transporters, cerebrospinal fluid, inhibitory neurotransmission, brain biomarkers, neuroinflammation, neurodegeneration, neuroprotection
- MeSH terms
- Aged, Alzheimer Disease, Brain, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Humans, Receptors, GABA, GABA Plasma Membrane Transport Proteins
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