You are viewing a javascript disabled version of the site. Please enable Javascript for this site to function properly.
Go to headerGo to navigationGo to searchGo to contentsGo to footer
In content section. Select this link to jump to navigation

The GABA–Working Memory Relationship in Alzheimer’s Disease


Alzheimer’s disease (AD) is a highly debilitating neurodegenerative disease with no cure to date. Emerging evidence indicates aberrations of the primary inhibitory neurotransmitter GABA in the frontal, parietal and temporal cortices, and hippocampal regions of the AD brains. GABA levels have been reported to predict working memory (WM) load capacity in the healthy young population. Since working memory is impaired in AD, it opens an active area of research to investigate the influence of GABA on WM performance in AD. Advancements in neuroimaging techniques and signal processing tools can aid in neurochemical profiling of GABA in AD as well as facilitate in probing the role of GABA in AD-specific impairments of working memory.

Alzheimer’s disease (AD) is a major neurodegenerative disease affecting millions of people worldwide [1]. Intensive basic and clinical research have yielded valuable information regarding AD-related structural aberrations, such as deposition of amyloid-β (Aβ) peptide and tau tangles [2], and neurochemical anomalies, such as dysfunction of acetylcholine and glutamate [3, 4]. Despite attempts on treating these structural and neurochemical pathologies, as evidenced from clinical trials attempting to reduce Aβ peptide production [5, 6] and pharmacological interventions targeting glutamatergic and cholinergic systems [7], cognitive deficits continue to persist and the cause of AD remains to be identified. Recently, animal and postmortem studies have elucidated a key involvement of the primary neuroinhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in AD pathology [8, 9]. Moreover, efforts are already under way in developing promising therapeutic strategies that target the GABAergic system in AD [10]. With GABA galvanizing support as a potential pathological factor and therapeutic approach in AD, it becomes worthwhile to investigate whether GABA is significantly involved in the cognitive deficits evident in AD. As a plethora of existing literature indicates a crucial role of GABA in working memory performance [11, 12], we posit a specific relationship between GABA aberrations and working memory impairments in AD patients.

GABA is widely spread in the mammalian brain and is believed to be involved in controlling cortical excitability [13]. Variations of GABA levels in AD brains has primarily been evidenced in postmortem and animal studies [14]. Initial postmortem studies report reduced GABA levels in the frontal, parietal and temporal cortices as compared to healthy age-matched controls [15]. Although most of these studies indicate no change in GABA levels in the hippocampus, a few studies have reported a reduction of GABA levels in this region [15, 16]. Recent studies based on AD mice models and postmortem human brain tissue have reported significantly higher GABA levels in the reactive astrocytes of the dentate gyrus region of the hippocampus [8, 9]. It is important to note that postmortem studies predominantly measure the activity of the synthesizing enzyme of GABA, namely glutamic acid decarboxylase (GAD). GAD is sensitive to the premortem conditions (e.g., hypoxia and hypovolemia) [17], and can thus introduce variability in the GABA levels quantified from postmortem brain tissues.

The advent of the non-invasive imaging technique, magnetic resonance spectroscopy (MRS), has provided researchers a reliable method to measure absolute GABA concentrations in various brain regions [18]. To the best of our knowledge, hitherto only one study has measured GABA levels (in relation to Creatine; GABA+/Cr) in AD patients using the MRS imaging modality [19]. The results from this study indicate significantly lower GABA+/Cr levels in the parietal region of AD patients as compared to age- and gender-matched healthy control subjects.

In the healthy population, the MRS technique has been used in conjunction with behavioral measures of WM [11, 12]. GABA levels from the dorsolateral prefrontal cortex (DLPFC) has been shown to initially increase and then decrease with repetitions of a WM task [11]. Furthermore, while attempting to parse out the association between GABA levels and WM in terms of the WM components (load, maintenance and distraction resistance) and the associated anatomical brain regions (DLPFC and visual cortex), GABA levels measured specifically from the DLPFC region has been reported to predict the load processing capacity of WM [12].

GABA levels have been associated with vascular factors, including perfusion changes [11], blood-oxygen-level dependent (BOLD) activity [20, 21] and the hemodynamic response function (HRF) [22]. Baseline GABA levels acquired from the DLPFC region have been indicated to correlate inversely with changes in DLPFC perfusion during the performance of a WM task [11]. Baseline GABA concentrations have been shown to correlate negatively with task-based positive BOLD response [21], and correlate positively with task-based negative BOLD response [20]. Task-based changes in GABA levels have also been indicated in functional MRI (fMRI) studies, such that the initial increase and then decrease in the GABA levels has been found to be negatively correlated with percentage BOLD signal change [23]. Higher GABA levels in the visual cortex have been indicated to have shorter and wider HRF distributions during the performance of a visual task [22]. Despite the abundance of research indicating a negative correlation between GABA levels and positive BOLD response, one recent study did not find a significant relation between baseline GABA concentrations and BOLD activations [24].

The emerging variety of measures and the accumulating empirical evidence for the role of GABA in WM open new avenues to investigate the link between GABA levels and aberrations of WM performance in the AD brain. Future studies are warranted to carry out longitudinal behavioral and vascular assessments of the GABA-WM relationship in mild cognitive impairment as well as early AD patients using advanced multimodal (MRS & fMRI) imaging modalities. It is also suggested that the influence of GABA on WM is assessed in terms of the distinct WM components. As research supports that working memory deficit in AD is multifactorial [25], the understanding of the GABA-WM relationship should be extended to incorporate potential mediating and/or moderating factors, such as Aβ aggregation and glutamatergic dysfunction [7]. Investigating the GABA-WM link will open further new pharmacological strategies aimed towards reducing, and perhaps even reversing, the working memory deficits prevalent in the escalating epidemic of AD.


The authors have no conflict of interest to report.


Dr. Pravat K. Mandal (Principal Investigator) thanks the Department of Biotechnology, Government of India for funding this research (Grant No. BT/PR7361/MED/30/953/2013). Financial support in the form of TATA Innovation Fellowship (Department of Biotechnology, Ministry of Science and Technology, Govt. of India) to Dr. Mandal is appreciated (Award No. BT/HRD/01/05/2015).



Prince M , Ali G-C , Guerchet M , Prina AM , Albanese E , Wu Y-T (2016) Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 8, 23–.


Bloom GS (2014) Amyloid-β and tau: The trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71, 505–508.


Schuff N , Capizzano AA , Du AT , Amend DL , O’Neill J , Norman D , Kramer J , Jagust W , Miller B , Wolkowitz OM , Yaffe K , Weiner MW (2002) Selective reduction of N-acetylaspartate in medial temporal and parietal lobes in AD. Neurology 58, 928–935.


Francis PT (2005) The interplay of neurotransmitters in Alzheimer’s disease. CNS Spectr 10, 6–9.


Imbimbo BP , Giardina GA (2011) gamma-secretase inhibitors and modulators for the treatment of Alzheimer’s disease: Disappointments and hopes. Curr Top Med Chem 11, 1555–1570.


Schor NF (2011) What the halted phase III gamma-secretase inhibitor trial may (or may not) be telling us. Ann Neurol 69, 237–239.


Nava-Mesa MO , Jimenez-Diaz L , Yajeya J , Navarro-Lopez JD (2014) GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer’s disease. Front Cell Neurosci 8, 167.


Jo S , Yarishkin O , Hwang YJ , Chun YE , Park M , Woo DH , Bae JY , Kim T , Lee J , Chun H , Park HJ , Lee DY , Hong J , Kim HY , Oh SJ , Park SJ , Lee H , Yoon BE , Kim Y , Jeong Y , Shim I , Bae YC , Cho J , Kowall NW , Ryu H , Hwang E , Kim D , Lee CJ (2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 20, 886–896.


Wu Z , Guo Z , Gearing M , Chen G (2014) Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model. Nat Commun 5, 4159.


Luo J , Lee SH , VandeVrede L , Qin Z , Piyankarage S , Tavassoli E , Asghodom RT , Ben Aissa M , Fa M , Arancio O , Yue L , Pepperberg DR , Thatcher GR (2015) Re-engineering a neuroprotective, clinical drugas a procognitive agent with high in vivo potency and with GABAApotentiating activity for use in dementia. BMCNeurosci 16, 67.


Michels L , Martin E , Klaver P , Edden R , Zelaya F , Lythgoe DJ , Luchinger R , Brandeis D , O’Gorman RL (2012) Frontal GABA levels change during working memory. PLoS One 7, e31933.


Yoon JH , Grandelis A , Maddock RJ (2016) Dorsolateral prefrontal cortex GABA concentration in humans predicts working memory load processing capacity. J Neurosci 36, 11788–11794.


Petroff OA (2002) GABA and glutamate in the human brain. Neuroscientist 8, 562–573.


Li Y , Sun H , Chen Z , Xu H , Bu G , Zheng H (2016) Implications of GABAergic neurotransmission in Alzheimer’s disease. Front Aging Neurosci 8, 31.


Lanctot KL , Herrmann N , Mazzotta P , Khan LR , Ingber N (2004) GABAergic function in Alzheimer’s disease: Evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry 49, 439–453.


Rossor MN , Iversen LL , Reynolds GP , Mountjoy CQ , Roth M (1984) Neurochemical characteristics of early and late onset types of Alzheimer’s disease. Br Med J (Clin Res Ed) 288, 961–964.


Reinikainen KJ , Paljarvi L , Huuskonen M , Soininen H , Laakso M , Riekkinen PJ (1988) A post-mortem study of noradrenergic, serotonergic and GABAergic neurons in Alzheimer’s disease. J Neurol Sci 84, 101–116.


Grewal M , Dabas A , Saharan S , Barker PB , Edden RA , Mandal PK (2016) GABA quantitation using MEGA-PRESS: Regional and hemispheric differences. J Magn Reson Imaging 44, 1619–1623.


Bai X , Edden RA , Gao F , Wang G , Wu L , Zhao B , Wang M , Chan Q , Chen W , Barker PB (2015) Decreased gamma-aminobutyric acid levels in the parietal region of patients with Alzheimer’s disease. J Magn Reson Imaging 41, 1326–1331.


Northoff G , Walter M , Schulte RF , Beck J , Dydak U , Henning A , Boeker H , Grimm S , Boesiger P (2007) GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nat Neurosci 10, 1515–1517.


Muthukumaraswamy SD , Edden RA , Jones DK , Swettenham JB , Singh KD (2009) Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans. Proc Natl Acad Sci U S A 106, 8356–8361.


Muthukumaraswamy SD , Evans CJ , Edden RA , Wise RG , Singh KD (2012) Individual variability in the shape and amplitude of the BOLD-HRF correlates with endogenous GABAergic inhibition. Hum Brain Mapp 33, 455–465.


Kuhn S , Schubert F , Mekle R , Wenger E , Ittermann B , Lindenberger U , Gallinat J (2016) Neurotransmitter changes during interference task in anterior cingulate cortex: Evidence from fMRI-guided functional MRS at 3 T. Brain Struct Funct 221, 2541–2551.


Harris AD , Puts NA , Anderson BA , Yantis S , Pekar JJ , Barker PB , Edden RA (2015) Multi-regional investigation of the relationship between functional MRI blood oxygenation level dependent (BOLD) activation and GABA concentration. PLoS One 10, e0117531.


Buckner RL (2004) Memory and executive function in aging and AD: Multiple factors that cause decline and reserve factors that compensate. Neuron 44, 195–208.