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Researchers are poised to conduct a first-of-its-kind clinical trial in India to investigate the effectiveness of administering the antioxidant glutathione orally against early Alzheimer's disease (AD).
The initiative aims to not only treat but also potentially delay the onset of the progressive neurological disease that destroys memory and other important mental functions and, eventually, the ability to carry out the simplest tasks.
Titled 'Impact of Glutathione (GSH) Supplementation in Mild Cognitive Impairment (MCI) Patients: A Randomized Control Trial', the study is funded by the Department of Biotechnology (DBT), approved by the Drugs Controller General of India and is listed on Clinical Trials Registry-India (CTRI).
Glutathione is a chemical and an antioxidant present in the brain. The brain consumes oxygen for its normal functioning and in the process, creates charged particles from metals, including iron, naturally present in the brain. These charged particles tend to combine to form radicals, which contribute to creating oxidative stress in the brain, which can damage brain cells, or neurons, resulting in their death.
Researchers now see promise in using glutathione, which they say has been shown to protect the brain in animal studies by counteracting these toxic radicals and preventing the forming of oxidative stress. The neurochemical is, thus, important for maintaining the brain's metabolic balance (homeostasis).
Oxidative stress has been researched to contribute significantly to mild cognitive impairment (MCI), characterised by low confidence in executing daily activities, repeating a certain phrase or question, and losing pleasure in daily activities and relationships. MCI can set in in one's 50s and can prevail for about 8 years before likely progressing to early AD.
The phase-3 clinical trial stands to provide direct evidence of glutathione's effects on the behaviours of MCI patients, who will be orally administered 500 milligrams of glutathione supplement every day for 6 months.
'As a scientist, I am hopeful and positive of people showing cognitive improvements after taking glutathione,' Pravat Mandal, senior scientist at the National Brain Research Centre (NBRC), Gurugram, and the principal investigator for the trial, told PTI in an interview.
If proven effective, the supplement could potentially benefit roughly 5 million Indians with mild cognitive impairment (MCI) and early Alzheimer's disease (AD). While the Alzheimer's Association, US, estimated 8.8 million Indians older than 60 years to have dementia earlier this year, AI studies have estimated the number to be from 8.8-10 million.
'We could be slowing the disease by 10-20 years if we can successfully intervene at this (MCI) stage,' Ashley Bush, professor of Psychiatry and Neuroscience, University of Melbourne, Australia, told PTI in an email.
MCI is the stage where oxidative stress starts to build up in the brain because of waning levels of the antioxidant glutathione, which happens with age.
Further, oxidative stress has been proven to facilitate the accumulation of strands of amyloid-beta proteins, normally present in the brain, to form amyloid plaques, which have classically been considered to be the cause and thus, the treatment target of Alzheimer's disease.
Mandal and his team have instead proposed that the forming of oxidative stress aided by glutathione deficiency should be addressed to treat Alzheimer's disease, and not amyloid plaque. They have recently published a paper to this effect in the journal ACS Chemical Neuroscience.
'As a neurosurgeon, I have frequently observed the consequences of oxidative stress in traumatic brain injuries, ruptured intracranial aneurysms (widening of blood vessels), and other major insults to the brain,' Joseph Maroon, clinical professor of neurological surgery at the University of Pittsburgh Medical Center, Pennsylvania, US, told PTI in an email.
Despite observed evidence, corroborated by autopsy studies of ageing brains and those with neurodegenerative disorders, data from clinical trials is imperative to support the glutathione deficiency and oxidative stress theory of AD.
'(Investigating oxidative stress for AD) is an approach that still warrants clinical trials,' said Bush.
In mice, glutathione administration has been shown to improve cognitive decline and depressive-like behaviours, even as the supplement's effects in humans are yet to be determined conclusively.
The absence of conclusive results through human trials is partly why despite being proven to precede amyloid accumulation, oxidative stress has not received as much attention as amyloid plaques have traditionally and historically received for treating Alzheimer's disease.
'Unlike plaques, oxidative stress is difficult to see down a microscope, so the theory has always been at a disadvantage psychologically in terms of popularity in the field. I think it has gained a respectable following that might be growing with time,' said Bush.
'Amyloid plaque is the effect, it is not the cause (of Alzheimer's disease),' said Mandal, also an adjunct professor of neurosurgery, the University of Pittsburgh, and senior research scientist at the Florey Institute of Neuroscience and Mental Health in Melbourne, where Bush is Mental Health Clinical Lead.
'The focus on removing amyloid plaque (as therapy) has consumed billions of dollars and to date has not been significantly effective in obviating (the disease) or even markedly improving the condition of patients,' said Maroon.
The recently published phase-3 clinical trials data of the drug donanemab, which targets amyloid plaque, have shown to reduce cognitive decline in AD patients, but also cause brain haemorrhage (bleeding) and edema (swelling) in some of these patients.
'We don't yet have a solution because no one cared to map iron levels in the brain,' said Mandal. He, along with Bush, Maroon, and others, have proposed the monitoring of the brain's glutathione and iron levels together as a biomarker for Alzheimer's disease.
Indian clinical trials could, therefore, nudge Alzheimer's disease researchers to look upstream at the stage preceding amyloid plaque for devising therapy, the experts said.
Bush described the proposed clinical trials on 50 individuals in India using glutathione therapy as 'very important and promising”.
'Years ago, there was a US phase 2 trial that treated AD patients with N-acetyl cysteine (NAC), a precursor to glutathione. While the patients definitely benefitted, it was a very small study. Had there been a handful more patients, (the study) may have been called 'significant' and the drug may already have been in use,' said Bush.
Clinical trials involving glutathione, however, are not without their fair share of challenges, one of which involves its administration. This is another reason why there have been few successful clinical trials globally.
Bush explained that injecting glutathione through veins, intravenous glutathione, is one of the solutions since glutathione taken orally is only digested and not absorbed. This presented a practical barrier to conducting successful clinical trials in Australia, he said.
Other challenges included the non-availability of substances, or precursors, that could produce glutathione in the body after administering them and insignificant amounts of these substances reaching the site of physiological activity after administration, Bush explained.
'N-acetyl cysteine is readily available. However, it doesn't enter the brain well. Other precursors that do pass into the brain have not been developed to the point where they are ready to be tested on humans,' said Bush.
In the US, while several studies have been performed administering glutathione in various preparations to MCI patients - intravenously, intranasally (through nose), and orally - to date, with the preparations used, results have not been conclusive so as to have reliable benefits, said Maroon.
However, the principal investigator of the proposed trial, is confident that orally administering 500 mg of glutathione will translate into cognitive improvements in patients.
The discovery of a form of cell death triggered because of its high iron content, called ferroptosis, has helped the oxidative stress approach gain more attention, according to Bush.
'(The discovery) has boosted interest since the death of the cell is induced by its own iron content (which damages cell membranes). It likely lies in the heart of many diseases, especially neurodegeneration,' said Bush.
However, unless clinical trial data do not become available, the approach will be devoid of a scientific endorsement and could continue to be the less-preferred therapeutic target for AD.
Clinical trial data from India could thus prove to be instrumental in taking forward the story of the oxidative stress hypothesis of Alzheimer's disease. The India trial was supposed to begin in January 2021 but hasn't started yet. The officials at NBRC declined to comment on the delay or the exact starting date of the trial.