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  • Systematic Review
  • Published:

The GABAergic system in Alzheimer’s disease: a systematic review with meta-analysis

Molecular Psychiatry volume 28, pages 5025–5036 (2023)Cite this article

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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 18th, 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABAA, GABAB, and GABAC 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 I2 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) < 0.001) and in the CSF (−0.41 [−0.72, −0.09], adj. p = 0.042), but not in the blood (−0.63 [−1.35, 0.1], adj. p = 0.176). In addition, GAD65/67 (−0.67 [−1.15, −0.2], adj. p = 0.006), GABAA 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 GABA levels in the CSF of AD patients. Our findings suggest the GABAergic system is vulnerable to AD pathology and should be considered a potential target for developing pharmacological strategies and novel AD biomarkers.

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Fig. 1: Flow diagram of study selection.
Fig. 2: GABA and GAD65/67 meta-analyses in the brain of AD patients compared to HC.
Fig. 3: GABAA receptor and GABA transporters meta-analyses in the brain of AD patients compared to HC.
Fig. 4: GABA levels in the CSF and blood of AD patients compared to HC.
Fig. 5: GABAergic system in AD brain.
Fig. 6: Proposed GABAergic synapse in AD brain.

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Data availability

All data are available on GitHub (bit.ly/3o5nqcn). Supplementary information is available at Molecular Psychiatry’s website.

Code availability

R codes generated in this work are available on GitHub (bit.ly/3o5nqcn).

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Acknowledgements

We thank Dr Gregor Gryglewski, who kindly provided the original meta-analysis R code, Dr Gabriel Pires, who helped with methodological questions during the planning and conduction of this work, Dr Victorio Bambini-Junior, who read the first drafts of the paper and provided thoughtful insights, and all the corresponding authors who clarified information on request. We thank BioRender.com for images used in Figs. 5 and 6. Any entity or organization has not directly funded this systematic review with meta-analysis.

Funding

GC-C has received funding from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) [88887.687008/2022-00]. BB receives financial support from CAPES [88887.336490/2019-00] and the Alzheimer’s Association (AA) [AARFD-22-974627]. PCLF has received funding from AA [AARFD-22-923814]. JPF-S receives financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [200691/2021-0]. JT is funded by the Canadian Institutes of Health Research (CIHR) doctoral award. CT is funded by the Fonds de Recherche du Québec – Santé (FRQS) doctoral award. MAB has received funding from CNPq PDJ [25/2021]. CS has received funding from CAPES [88887.696202/2022-00] and CNPq [141357/2020-7]. TAP is supported by AA [AACSF-20-648075] and the National Institute of Aging [R01AG075336; R01AG073267]. PR-N receives funding from CIHR [MOP-11-51-31 and RFN 152985; 159815; 162303], the Canadian Consortium of Neurodegeneration and Aging (CCNA) [MOP-11-51-31], the Weston Brain Institute, AA [NIRG-12-92090; NIRP-12-259245], the Brain Canada Foundation [34874 and 33397], FRQS [2020-VICO-279314], and Colin J. Adair Charitable Foundation. DOS is supported by CNPQ/INCT [465671/2014-4], CNPQ/FAPERGS/PRONEX [16/2551- 0000475-7], and FAPERGS [19/2551-0000700-0]. ERZ receives financial support from CNPq [312410/2018-2; 435642/2018-9; 312306/2021-0; 409066/2022-2], ARD/FAPERGS [21/2551-0000673-0], AA [AARGD-21-850670], CNPQ/FAPERGS/PRONEX [16/2551-0000475-7], the Brazilian National Institute of Science and Technology in Excitotoxicity and Neuroprotection [465671/2014-4], Instituto Serrapilheira [Serra-1912-31365], and AA and National Academy of Neuropsychology [ALZ-NAN-22-928381]. The funders had no role in the elaboration of the protocol, data collection and analysis, and manuscript preparation.

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Authors and Affiliations

  1. Graduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Institute of Health Basic Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90035-003, Brazil

    Giovanna Carello-Collar, Bruna Bellaver, João Pedro Ferrari-Souza, Vanessa G. Ramos, Carolina Soares, Diogo O. Souza & Eduardo R. Zimmer

  2. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Bruna Bellaver, Pamela C. L. Ferreira, João Pedro Ferrari-Souza, Carolina Soares & Tharick A. Pascoal

  3. McGill Centre for Studies in Aging, McGill University, Montreal, QC, H4H 1R3, Canada

    Joseph Therriault, Cécile Tissot, Pedro Rosa-Neto & Eduardo R. Zimmer

  4. Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, H4H 1R3, Canada

    Joseph Therriault, Cécile Tissot, Pedro Rosa-Neto & Eduardo R. Zimmer

  5. Departments of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 1A1, Canada

    Joseph Therriault, Cécile Tissot & Pedro Rosa-Neto

  6. Department of Pharmacology, Institute of Health Basic Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90035-003, Brazil

    Marco A. De Bastiani & Eduardo R. Zimmer

  7. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Tharick A. Pascoal

  8. Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada

    Pedro Rosa-Neto

  9. Department of Biochemistry, Institute of Health Basic Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90035-003, Brazil

    Diogo O. Souza

  10. Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Department of Pharmacology, Institute of Health Basic Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90035-003, Brazil

    Eduardo R. Zimmer

  11. Brain Institute of Rio Grande Do Sul, Pontifical Catholic University of Rio Grande Do Sul, Porto Alegre, RS, 90610-000, Brazil

    Eduardo R. Zimmer

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  1. Giovanna Carello-Collar
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Contributions

Study conception and design: GC-C, BB, CS, and ERZ. Paper screening and data extraction: GC-C, PCLF, JPF-S, and VGR. Data preparation: GC-C and BB. Meta-analysis: GC-C, BB, and MAB. Data interpretation: GC-C, BB, and ERZ. Manuscript preparation and figure elaboration: GC-C. Intellectual content: GC-C, BB, PCLF, JPF-S, VGR, JT, CT, MAB, CS, TAP, PR-N, DOS, ERZ. All authors revised and approved the final version of the paper.

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Correspondence to Eduardo R. Zimmer.

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Competing interests

ERZ serves on the scientific advisory board of Next Innovative Therapeutics (Nintx). The other authors declare no competing interests.

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Carello-Collar, G., Bellaver, B., Ferreira, P.C.L. et al. The GABAergic system in Alzheimer’s disease: a systematic review with meta-analysis. Mol Psychiatry 28, 5025–5036 (2023). https://doi.org/10.1038/s41380-023-02140-w

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