Aging takes a toll on all of the body’s tissues, and the brain is no exception. Struggling with memory, mental math, and finding the right word can be more than forgetfulness. When these cognitive abilities become hampered to the point where daily life is affected, patients may be diagnosed with cognitive impairment. Unfortunately, although its symptoms are simple to describe and easy to diagnose, cognitive impairment is an extremely difficult condition to treat owing to its irreversible and brain-wide nature. Additionally, cognitive impairment typically continues to get worse over time and, in some cases, may eventually progress to more serious ailments such as Alzheimer’s disease.
Due to this progression and the emotional and functional difficulties that accompany the condition, doctors and patients put preventing or ameliorating cognitive impairment at a premium. The longer patients can maintain good cognitive function, the longer they can be independent and enjoy a high quality of life. However, there is no single approved treatment to slow down or stop cognitive impairment before escalation to an Alzheimer’s disease diagnosis, however. This means that patients who are interested in protecting their cognition are increasingly looking outside of the boundaries of mainstream medicine to optimize their cognitive health. Today, many supplements and alternative therapies claim to alleviate cognitive impairment, yet few are currently proven to be more effective than placebo. But there are promising options. For many, glutathione supplementation may a particularly attractive choice due to its minimal side effect profile and proven link to cognitive functioning in both healthy people and people with cognitive impairment.
What is Glutathione?Glutathione is a common physiological molecule with a panorama of essential roles within most multicellular organisms. In humans, glutathione is used in many fundamental metabolic processes ranging from the nitric oxide cycle to dietary mineral incorporation. Additionally, glutathione is instrumental for cells to regulate their division and their differentiation from progenitor cells into mature somatic cells responsible for carrying out bodily processes.
During cellular differentiation, stem cells receive chemical signals like glutathione, causing them to change their characteristics to transform into the kind of cell the body needs. As this differentiation process continues, the stem cells become progenitor cells which are more similar to the intended cell type. Toward the end of the differentiation process, cells migrate to the location where they will reside in the body and complete the final touches necessary for maturation.
Glutathione is also one of the body’s core antioxidants and binds circulating reactive oxygen species (ROS) which can cause cellular and DNA damage if left unchecked. Reactive oxygen species, also known as free radicals, are byproducts of metabolism which are broadly harmful. To scavenge circulating ROS, glutathione binds ROS to itself, becoming oxidized. This means that glutathione prevents important cellular proteins or DNA from being oxidized, which can inhibit their function.
Due to its versatility, glutathione can also play this role for a number of other detrimental chemicals. Research has linked glutathione to a number of non-ROS detoxification processes as well as immune cell function and the regulation of induced cell death. Glutathione is a good candidate for treating cognitive impairment because it has been studied within that context extensively owing to the relationship between cognitive impairment and oxidative stress. Furthermore, glutathione’s critical role in a multitude of physiological processes can likely support many separate cognitive functions even in the absence of oxidative stress.
Understanding the Causes of Cognitive Impairment
In the absence of traumatic brain injury, an underlying psychiatric disorder, or chemotherapy, there is typically no single identifiable root cause of cognitive impairment. However, one of the primary molecular mechanisms of cognitive impairment is oxidative stress. This oxidative stress activates many other mechanisms associated with cognitive impairment, including inflammation and cell death signals while interfering with the functioning of many cellular and molecular processes.
As with many pathologies associated with aging, oxidative stress—and thus, cognitive impairment—slowly builds as a result of the aging process, exposure to chemical stressors, parasympathetic nervous system activation, and unrepaired stress damage. Antioxidants and molecules which help the brain cope with oxidative stress like glutathione are therefore excellent candidates for cognitive impairment treatments, whether preventively or therapeutically. By intervening before reactive oxygen species can cause damage to neurons, these chemicals lighten the load and allow cells to catch up on repairing old damage that they may be too overwhelmed to address. Such built-up damage is one of the major causes of age-related impairment.
As the brain ages, neurons are less capable of forming connections to one another as this damage mounts. Because neurons can’t form or strengthen connections to one another as easily, learning becomes more difficult. Simultaneously, neuronal death and degeneration accelerate with age, eventually resulting greater cognitive impairment. Depending on the location within the brain that experiences neuronal death, different symptoms of cognitive impairment occur; the most notable symptoms of cognitive impairment, like difficulty with memory recall, are a result of dying neurons within the temporal lobes. Likewise, if neurons within Broca’s area or Wernicke’s area die, patients exhibit difficulty finding the right words and processing their thoughts into narratives. Should neurons in the ventral tegmental area die, patients experience anhedonia and difficulty with initiating behaviors.
Cognitive impairment is often—but not always—associated with subsequent development of Alzheimer’s disease. One research paper goes as far as to say that cognitive impairment is biologically indistinguishable from early-stage Alzheimer’s disease. In Alzheimer’s disease, cognitive impairment is a major symptom which steadily worsens until dementia sets in and the patient’s cognition is entirely compromised. In cognitive impairment caused by Alzheimer’s, patients’ brains are gradually damaged by beta-amyloid plaques. Once these plaques are established, there’s no known way of removing them.
Exploring Glutathione’s Impact On Cognition
Glutathione has been implicated as a critical factor in the cognitive impairment of Alzheimer’s disease as well as non-Alzheimer’s cognitive impairment owing to its ability to help the body cope with oxidative stress. In the context of Alzheimer’s, while glutathione can’t remove beta-amyloid plaques, it can address the added stress that these plaques produce.
Due to the diminished levels of glutathione in those with cognitive impairment, however, patients are left without the protection offered by the molecule. In a study assaying glutathione concentrations in the blood plasma of Alzheimer’s disease patients and patients with mild cognitive impairment, all 25 patients with mild cognitive impairment and all 63 patients with Alzheimer’s disease had glutathione levels which were markedly lower than the study’s 53 control patients. Importantly, the study did not examine whether the glutathione molecules had scavenged reactive oxygen species at the time of measurement, necessitating further research.
This study was subsequently elaborated upon in by another research cohort in 2014, which found that increased ratios of oxidized glutathione to its unoxidized state in the anterior and cingulate cortices of the brain were associated with increased symptoms of cognitive impairment. Patients from the study who were diagnosed with mild cognitive impairment had 2.2 to 2.9 times as much oxidized glutathione in their brain as the healthy controls, though the authors of the study did not publish the absolute quantities of glutathione in either state. This means that both the location and oxidation state of high glutathione concentrations are critical diagnostically.
High concentrations of oxidized glutathione in the brain are evidence that the brain is in a compromised state, but high concentrations in the blood plasma are healthy and normal. The reasoning behind this is that oxidized glutathione must return to the bloodstream from the brain in order to discharge the ROS it carries into a metabolic process which can make use of them constructively. As such, high concentrations of oxidized glutathione in the brain may mean that there is not enough glutathione to remove all of the reactive oxygen species that are circulating, indicating severe levels of stress.
Given that oxidative stress may be partially controlled by glutathione according to the literature cited above, many researchers are interested in investigating whether glutathione can be harnessed to improve cognitive outcomes in brain disorders which traditionally coincide with high levels of oxidative stress. To date, glutathione has been explicitly investigated as a therapy for the oxidative stress-driven cognitive impairment caused by Alzheimer’s disease in a 2012 review. The review favorably discusses the potential for glutathione therapy to reduce cognitive impairment via its ability to scavenge reactive oxygen species in the brain. Scavenging reactive oxygen species is important because many of the critical enzymes in neurons are easily oxidized, impairing their function in multiple ways. Most importantly, oxidation at the enzyme’s reaction site may prevent the enzyme from performing its primary task entirely. In other cases, enzymes may be oxidized elsewhere and merely have their functionality partially impaired. In rare cases, oxidation could theoretically change the output of the enzyme’s primary reaction, which would have unpredictable physiological results.
In one study discussed by the review, researchers attempted to see whether glutathione infusion could be used to rescue cells which had been artificially stressed by reactive oxygen species and various other toxins in vitro. When glutathione molecules were infused into neurons exhibiting high levels of neuronal damage and stress, their concentration of signaling molecules associated with cellular stress was reduced by 50%. This effect was consistent even when researchers infused three times as much of their “stress mix” as would be realistically found in a cognitive impairment patient in vivo. This suggests that glutathione supplementation could be a viable treatment for reducing symptoms of cognitive impairment and potentially preventing progression.
The Potential of Glutathione Supplementationhighly bioavailable glutathione supplements contained in sophisticated delivery systems which can traffic the molecule through the first-pass of metabolism. These delivery systems will likely incorporate nanotechnology which encapsulates glutathione in a sphere of fat molecules. After surviving the first-pass metabolism, the glutathione supplement will need to find a way to cross the blood-brain-barrier such that it can subsequently scavenge reactive oxygen species and mitigate cognitive impairment.
With the right glutathione supplement, patients can potentially increase their brain’s concentrations of glutathione sufficiently to address some levels of cognitive impairment. Currently, glutathione supplementation is under active research by leading scientists within the field of Alzheimer’s studies and geriatrics, which means that more data supporting its use should be actively forthcoming. In the meantime, patients can use glutathione supplementation to proactively protect their brain from the ravages of cognitive impairment.
Duffy SL, Lagopoulos J, Hickie IB, Diamond K, Graeber MB, et al. 2014. Glutathione relates to neuropsychological functioning in mild cognitive impairment. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association; 10:67–75. http://www.alzheimersanddementia.com/article/S1552-5260(13)00037-X/abstract
Lu SC. 2013. Glutathione synthesis. Biochim Biophys Acta; 1830:3143–3153. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549305/
Padurariu M, Ciobica A, Hritcu L, Stoica B, Bild W, et al. 2010. Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer’s disease. Neuroscience Letters; 469:6–10. http://www.sciencedirect.com/science/article/pii/S0304394009014992
Pocernich CB, Butterfield DA. 2012. Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease; 1822:625–630. http://www.sciencedirect.com/science/article/pii/S0925443911002262.
Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF. 2003. The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol. 66:1499–1503. https://www.ncbi.nlm.nih.gov/pubmed/14555227
Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, et al. 2003. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiology of Aging; 24:915–919. http://www.neurobiologyofaging.org/article/S0197-4580(03)00031-9/abstract