GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer's disease

Topic: Gut, metabolism and diet

In this review, we focus on the potential role of the γ-aminobutyric acidergic (GABAergic) system in age-related episodic memory impairments in humans, with a particular focus on Alzheimer's disease (AD). Well-established animal models have shown that GABA plays a central role in regulating and synchronizing neuronal signaling in the hippocampus, a brain area critical for episodic memory that undergoes early and significant morphologic and functional changes in the course of AD. Neuroimaging research in humans has documented hyperactivity in the hippocampus and losses of resting state functional connectivity in the Default Mode Network, a network that itself prominently includes the hippocampus-presaging episodic memory decline in individuals at-risk for AD. Apolipoprotein ε4, the highest genetic risk factor for AD, is associated with GABAergic dysfunction in animal models, and episodic memory impairments in humans. In combination, these findings suggest that GABA may be the linchpin in a complex system of factors that eventually leads to the principal clinical hallmark of AD: episodic memory loss. Here, we will review the current state of literature supporting this hypothesis. First, we will focus on the molecular and cellular basis of the GABAergic system and its role in memory and cognition. Next, we report the evidence of GABA dysregulations in AD and normal aging, both in animal models and human studies. Finally, we outline a model of GABAergic dysfunction based on the results of functional neuroimaging studies in humans, which have shown hippocampal hyperactivity to episodic memory tasks concurrent with and even preceding AD diagnosis, along with factors that may modulate this association.

Key findings

• Well-established animal models have shown that GABA plays a central role in regulating and synchronizing neuronal signaling in the hippocampus, a brain area critical for episodic memory that undergoes early and significant morphologic and functional changes in the course of AD.
• Apolipoprotein ε4, the highest genetic risk factor for AD, is associated with GABAergic dysfunction in animal models, and episodic memory impairments in humans.
• In combination, these findings suggest that GABA may be the linchpin in a complex system of factors that eventually leads to the principal clinical hallmark of AD: episodic memory loss.
• Finally, we outline a model of GABAergic dysfunction based on the results of functional neuroimaging studies in humans, which have shown hippocampal hyperactivity to episodic memory tasks concurrent with and even preceding AD diagnosis, along with factors that may modulate this association.

New to this subject? Start with our plain-English guide: Digital health →

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.semcdb.2021.01.005
• PubMed: 33573856
• Original source →

Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.

@article{jimenezbalado2021-33573856,
  author  = {Jiménez-Balado, J. and Eich, T. S.},
  title   = {{GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer's disease}},
  journal = {Seminars in cell \& developmental biology},
  year    = {2021},
  doi     = {10.1016/j.semcdb.2021.01.005},
  pmid    = {33573856},
  url     = {https://doi.org/10.1016/j.semcdb.2021.01.005}
}

Related studies in Digital health tools

• Interferon γ: a master cytokine in microglia-mediated neural network dysfunction and neurodegeneration Trends in neurosciences · 2022-10-22 · usefulness score 40/100
• Aging, mitochondrial dysfunction, and cerebral microhemorrhages: a preclinical evaluation of SS-31 (elamipretide) and development of a high-throughput machine learning-driven imaging pipeline for cerebromicrovascular protection therapeutic screening GeroScience · 2025-04-02 · usefulness score 43/100
• Diagnosis of Alzheimer's Disease via Multi-Modality 3D Convolutional Neural Network Frontiers in neuroscience · 2019-05-31 · usefulness score 53/100
• Functional neural network analysis in frontotemporal dementia and Alzheimer's disease using EEG and graph theory BMC neuroscience · 2009-08-21 · usefulness score 47/100
• Transformer-based deep neural network language models for Alzheimer's disease risk assessment from targeted speech BMC medical informatics and decision making · 2021-03-09 · usefulness score 47/100
• Interpretable classification of Alzheimer's disease pathologies with a convolutional neural network pipeline Nature communications · 2019-05-15 · usefulness score 45/100

Similar studies

• Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment 2013 · Digital health tools
• GABAergic Inhibitory Interneuron Deficits in Alzheimer's Disease: Implications for Treatment 2020 · Digital health tools
• GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease 2014 · Inflammation and the immune system
• Relationships between β-amyloid and functional connectivity in different components of the default mode network in aging 2011 · Brain scans and imaging
• Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer's disease 2011 · Down syndrome and Alzheimer's
• Functional alterations in memory networks in early Alzheimer's disease 2010 · Brain scans and imaging

More on Digital health tools

• A review that covers this ground Episodic memory in normal aging and Alzheimer disease: Insights from imaging and behavioral studies Ageing research reviews · 2015-08-28 · usefulness score 36/100
• Newest in this subject Speaker-Wise Dementia Screening fromNaturalistic Speech with Lexical Entropy, Semantic Drift, and Multimodal Fusion Research Square · 2026-10-21 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Integrating Multisource Target Evidence with Machine-Learning Potency Prediction for Alzheimer’s Disease Drug Discovery bioRxiv · 2026-10-20 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Digital health tools →