Altered central and blood glutathione in Alzheimer’s disease

26 January 2025
Dr Fahd Al Qureshah
Altered central and blood glutathione in Alzheimer’s disease

Background

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 70% of cases globally. Its hallmark features include amyloid-beta plaques, neurofibrillary tangles, and progressive neurodegeneration, with mild cognitive impairment (MCI) often serving as a precursor. Despite the availability of treatments for AD, their efficacy is limited, prompting researchers to explore alternative mechanisms such as oxidative stress (OS). OS plays a key role in neurodegeneration, and glutathione (GSH), a critical antioxidant involved in mitochondrial function and cellular defense, is a candidate biomarker and therapeutic target. This study aimed to evaluate in vivo GSH levels in the brain and blood of individuals with AD or MCI compared to healthy controls (HC) through a systematic review and meta-analysis.


Objective

The study aimed to quantify the differences in GSH levels between individuals with AD, MCI, and HC, focusing on both brain and blood compartments. By synthesizing data from numerous studies, the researchers sought to clarify the potential role of GSH as a biomarker for oxidative stress in cognitive impairment and neurodegeneration.


Methods

Search Strategy:

  • Data was gathered from multiple databases, including MEDLINE, Embase, and others, covering studies published from 1947 to June 2020.

Inclusion Criteria:

  • Studies that measured GSH levels in the brain or blood (serum, plasma, or intracellular) of AD or MCI participants compared to HC.
  • Use of clinical diagnostic criteria for AD or MCI.

Statistical Analysis:

  • Random-effects models calculated standardized mean differences (SMDs) with 95% confidence intervals (CIs).
  • Heterogeneity was assessed using the Q statistic and I² index.
  • Publication bias was evaluated through Egger’s test.

Data Pool:

  • The analysis included data from 4 brain-focused studies (135 AD and 223 HC participants; 213 MCI and 211 HC participants) and 26 blood-focused studies (1203 AD and 1135 HC participants; 434 MCI and 408 HC participants).


Results

1. Brain GSH Levels

  • No significant difference was observed in overall brain GSH levels between AD and HC (SMD = 0.07, p = 0.92) or between MCI and HC (SMD = -0.43, p = 0.26).
  • However, when only studies using the MEGA-PRESS acquisition method were analyzed, significant reductions in GSH were observed:
  • AD vs. HC: SMD = -1.45, p < 0.001.
  • MCI vs. HC: SMD = -1.15, p < 0.001.
  • These findings highlight the importance of standardized, sensitive methods like MEGA-PRESS in detecting GSH alterations.

2. Blood GSH Levels

  • Significant reductions in blood GSH levels were observed in both AD and MCI:
  • AD: SMD = -0.87, p < 0.001.
  • MCI: Intracellular GSH was significantly lower (SMD = -0.66, p = 0.025), while total blood GSH showed no significant reduction (SMD = -0.40, p = 0.14).
  • In AD, both intracellular (SMD = -0.80, p = 0.004) and extracellular GSH (SMD = -0.86, p = 0.007) were significantly reduced.

3. Heterogeneity and Bias

  • Substantial heterogeneity was noted in most analyses (e.g., I² = 95.4% for blood GSH in AD), reflecting variability in study designs and measurement methods.
  • Egger’s test revealed potential publication bias, particularly in blood GSH studies for AD (bias = -5.18, p = 0.035).

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Discussion

The meta-analysis provides evidence for altered GSH levels in both the brain and blood of individuals with AD and MCI:

  • Brain GSH: Significant reductions were only evident when using standardized protocols like MEGA-PRESS, suggesting the need for consistent measurement techniques.
  • Blood GSH: Reductions in intracellular GSH were observed earlier in MCI, while both intracellular and extracellular GSH were affected in AD. This suggests a progressive depletion of antioxidant defenses as cognitive impairment advances.

The findings support the hypothesis that oxidative stress, reflected by reduced GSH levels, contributes to neurodegeneration. GSH depletion in the intracellular compartment of MCI participants indicates early involvement of oxidative mechanisms in cognitive decline.


Implications

Diagnostic Potential:

  • GSH may serve as a biomarker for early detection of MCI and progression to AD, especially when using sensitive measurement techniques like MEGA-PRESS.
  • Intracellular GSH depletion in blood offers a minimally invasive diagnostic avenue.

Therapeutic Opportunities:

  • Enhancing GSH levels could mitigate oxidative stress and slow neurodegeneration.
  • Future research should explore GSH supplementation or other antioxidant therapies as potential treatments.

Standardization and Future Research:

  • The study emphasizes the need for standardized GSH measurement techniques to reduce variability and improve the reliability of findings.
  • Longitudinal studies are necessary to assess the temporal relationship between GSH depletion and cognitive decline.
  • Sex-based differences in GSH metabolism should be investigated further, as male participants in the included studies exhibited greater reductions in GSH.


Conclusion

This meta-analysis highlights the potential of GSH as both a biomarker and therapeutic target in AD and MCI. While reductions in GSH are more pronounced in advanced stages of cognitive impairment, intracellular GSH depletion in MCI underscores its early role in oxidative stress-related neurodegeneration. Future research should aim to standardize measurement protocols, explore sex differences, and investigate long-term therapeutic strategies to enhance GSH levels.


For full details, refer to the original article: https://pubmed.ncbi.nlm.nih.gov/35123548/