Hope for Alzheimer’s: Can a new test on iron and glutathione levels hold the key to early diagnosis?

Our preliminary study looked at the levels of iron and glutathione in the brain and blood of healthy subjects; data for the levels in those with early stages of Alzheimer’s is already available in literature.

What we found is that as long as you are healthy — no matter what your age — the blood levels of glutathione and iron remain almost the same. The iron levels do go up a little after the age of 50 years, but it is not significant. In Alzheimer’s patients, however, both iron and glutathione levels go down significantly.

The discovery has been made but now we need to validate the tests across various patient populations and fix a protocol so that we can have a marker with high sensitivity and specificity. Now, we will begin a pilot study at Medanta hospital to verify these findings and gain broader acceptance for it.

What is the theory for Alzheimer’s disease that your team is working on?

The actual cause of Alzheimer’s disease is not really known; many teams are working on different theories. Our team with clinical studies on Alzheimer’s patients has shown that iron deposition in the hippocampus along with decrease in the levels of the antioxidant glutathione in the same area of the brain is one of the important factors of the disease.

What we know so far is that glutathione is a master antioxidant; it neutralises any free radicals generated by excess iron in the brain. However, when there is an increase in the iron levels and a decrease in the levels of glutathione in the brain,  it causes the dysfunction.

Another study from the team has established the relationship between the levels of iron and glutathione in the brain with that in the blood as mentioned earlier. Now, why does the iron level go down in the blood even as it goes up in the brain? I can’t answer that at this moment. We do not know the mechanism yet. Our team has been more focussed on studying the mechanisms in the brain but we will study the blood more in the future.

We looked at the blood only because we wanted to find a marker in the peripheral system so that we can at least screen people who are at a higher risk to develop the neurodegenerative disease.

Now, once we do detect people who are at a higher risk of developing the disease, what can be done to change the progression?

It would be very irresponsible to tell people they are at a high risk of a disease if there aren’t any possible avenues for them to prevent the progression or at least stay at the same level of cognition. The good thing is the tests are mechanistically related to the disease.

What this means is that the iron and glutathione levels are actually related to the cause of the disease. Take for example flu, you might get a fever or body ache but treating the symptoms doesn’t help, we have to treat the virus that is causing it.

What we have seen is that the glutathione levels in the hippocampus start dipping first and then the iron levels increase subsequently. So, the hypothesis is that in the early stages of the disease, when a person has mild cognitive impairment, if a person starts taking glutathione and at the same time takes an iron chelator to reduce the iron levels, it is likely to prevent progression. So, the patients can remain in the transitional phase for years and do not go on to Alzheimer’s. To study this, our team has registered another trial.

The leading theory on Alzheimer’s is that it is caused by abnormal clumping of amyloid beta protein. Three drugs have been approved over the last two years by the US FDA based on this theory. Is this right or wrong?

Amyloid theories have been the dominant one for nearly 25 to 30 years; the amyloid beta plaques are what the brain scans pick up in the Alzheimer’s patients. But people have been rethinking the theory — studies have been published showing similar amyloid clumping in autopsies of absolutely healthy people with no cognitive impairment.

A study from University of Irvine also quotes our findings stating that these redox changes precede the amyloid plaque formation.

Now, you mentioned the three drugs. So, you would know that these come with the serious side effects called Amyloid-related imaging abnormalities (ARIA) — swelling and bleeding in the brain. Significant atrophy in the hippocampus has also been observed in people on the drug. Of course, the success of the drugs in slowing cognitive decline came as a hope for many but considering the cost of the drugs and the side-effects, we really need to see what the long-term benefits would be.

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Why Professor Mandal? He is a senior scientist and former director-in-charge of the National Brain Research Centre. His work focusses on early diagnostic markers of Alzheimer’s, neuroimaging techniques, and brain chemistry in people with neurological and psychiatric disorders. Alumnus of IIT Madras, he has worked with the department of radiology at Johns Hopkins and department of psychiatry and anaesthesia at University of Pittsburgh. He has published at least 65 papers in high impact international journals.