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

Molecular Psychiatry (2024)Cite this article

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Abstract

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. 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 (PROSPERO #CDRD42022299518). 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 I2 statistics. 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; I2 = 74.54%; P < 0.001) and aspartate levels (SMD = −0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = −0.75; I2 = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = −0.63; I2 = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = −0.60; I2 = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = −1.07; I2 = 41.81%; 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. 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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Fig. 1: Study selection.
Fig. 2: Forest plots of included studies evaluating glutamate reuptake, transporters, storage, recycling, and aspartate.
Fig. 3: Forest plots of included studies evaluating glutamate receptors.
Fig. 4: Summary of changes in the glutamatergic system in the AD brain.

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Scripts used for statistical analysis will be provided upon reasonable request.

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Acknowledgements

We would like to thank Dr. Grylewsky for the statistical support and assistance in writing the RStudio script.

Funding

C.S. has received funding from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) [88887.696202/2022-00] and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [141357/2020-7]. A.R. is supported by CNPq [165626/2017–8 and 141254/2019–0] and Fulbright 2021 DDRA Award. G.C-C. has received funding from CAPES [88887.687008/2022-00]. G.L. has received funding from CAPES [88887.687008/2021-00]. L.M. has received funding from CAPES [88887.687008/2020-00]. B.B. has received financial support from CAPES [88887.336490/2019-00] and the Alzheimer’s Association (AA) [AARFD-22-974627]. J.P.F-S. receives financial support from CNPq [200691/2021-0]. M.A.B. has received funding from CNPq PDJ [25/2021]. T.A.P. is supported by AA [AACSF-20-648075] and the National Institute on Aging [R01AG075336; R01AG073267]. P.R-N. receives funding from Canadian Institute of Health Research [MOP-11-51-31 and RFN 152985; 159815; 162303], the Canadian Consortium of Neurodegeneration and Aging, the Weston Brain Institute, AA [NIRG-12-92090; NIRP-12-259245], the Brain Canada Foundation [34874 and 33397], and the Fonds de recherche en santé du Québec [2020-VICO-279314]. D.O.S. is supported by CNPQ/INCT [465671/2014-4], CNPQ/FAPERGS/PRONEX [16/2551- 0000475-7], and FAPERGS [19/2551-0000700-0]. E.R.Z. receives financial support from CNPq [312410/20182; 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 National Academy of Neuropsychology [ALZ-NAN-22-928381].

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Authors and Affiliations

  1. Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Carolina Soares, Lucas Uglione Da Ros, Luiza Santos Machado, Andreia Rocha, Gabriela Lazzarotto, Giovanna Carello-Collar, João Pedro Ferrari-Souza, Diogo O. Souza, Bruna Bellaver & Eduardo R. Zimmer

  2. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Carolina Soares, João Pedro Ferrari-Souza, Firoza Z. Lussier, Tharick A. Pascoal & Bruna Bellaver

  3. Graduate Program in Biological Sciences: Pharmacology and Therapeutics, UFRGS, Porto Alegre, Brazil

    Marco A. De Bastiani & Eduardo R. Zimmer

  4. Department of Biochemistry, UFRGS, Porto Alegre, Brazil

    Diogo O. Souza & Eduardo R. Zimmer

  5. Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada

    Pedro Rosa-Neto

  6. Douglas Research Institute, Le Centre Intégré Universitaire de Santé et de Services Sociaux de l’Ouest-de-l’Île-de-Montréal, McGill University, Montreal, QC, Canada

    Pedro Rosa-Neto

  7. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Pedro Rosa-Neto, Tharick A. Pascoal & Eduardo R. Zimmer

  8. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Pedro Rosa-Neto

  9. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

    Tharick A. Pascoal

  10. Brain Institute of Rio Grande do Sul - Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    Eduardo R. Zimmer

  11. Department of Pharmacology, UFRGS, Porto Alegre, Brazil

    Eduardo R. Zimmer

Authors
  1. Carolina Soares
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  2. Lucas Uglione Da Ros
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  14. Eduardo R. Zimmer
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Contributions

Study conception and design: C.S., G.C-C., B.B., and E.R.Z. Article screening and data extraction: C.S, L.U.dR., L.M., A.R. and G.L. Data preparation: C.S. and B.B. Meta-analysis: C.S. and M.A.B. Data interpretation: C.S., B.B. and E.R.Z. Manuscript preparation and figure elaboration: C.S. Intellectual content: all authors. All authors revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Eduardo R. Zimmer.

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Competing interests

E.R.Z. served in the SAB of Novo Nordisk, serves on SAB of Next Innovative Therapeutics (Nintx) and serves on the SAB and is a Co-founder of MASIMA. P.R-N. served in the SAB of Novo Nordisk, Eisai and Ely Lilly and as a Consultant in Eisai and Cerveau radiopharmaceuticals. Other authors declare no conflict of interest.

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Soares, C., Da Ros, L.U., Machado, L.S. et al. The glutamatergic system in Alzheimer’s disease: a systematic review with meta-analysis. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02473-0

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