Scientifically Speaking | How we got Alzheimer’s disease all wrong

Published on Jun 08, 2022 12:00 PM IST
  • Despite the intense focus, no effective treatments exist for the disease. It is time to cast a wider net and focus on alternative theories on what causes Alzheimer’s disease and how it can be treated
A significant number of people who have been diagnosed with Alzheimer’s don’t have the plaques (that were supposed to be the landmark characteristic) and around a third of elderly adults have plaques without having Alzheimer’s. (Shutterstock) PREMIUM
A significant number of people who have been diagnosed with Alzheimer’s don’t have the plaques (that were supposed to be the landmark characteristic) and around a third of elderly adults have plaques without having Alzheimer’s. (Shutterstock)
ByAnirban Mahapatra

A research article published in Nature Neuroscience on June 2 adds to mounting evidence that decades of trying to treat Alzheimer’s disease by focusing exclusively on one approach known as the “amyloid hypothesis” may not lead to effective cures for everyone. Researchers focused on this one treatment method for decades. Billions of dollars were spent.

But despite the intense focus, no effective treatments exist for Alzheimer’s disease. It is time for science to cast a wider net and to focus on alternative theories on what causes Alzheimer’s disease and how it can be treated.

Alzheimer’s disease is an irreversible and debilitating disease which causes mental decline, short-term memory loss, problems with speech, and difficulty in performing routine activities. It is primarily a disease of the elderly, and it affects millions of people worldwide.

Since its discovery over a century ago, Alzheimer’s disease has been characterised by the presence of plaques in the brain made of a protein called amyloid-beta (or amyloid, for short). The prevailing wisdom has been that the accumulation of amyloid in plaques is what leads to the progression of Alzheimer’s disease.

In addition to plaques made of amyloid, researchers have shown that there are tangles of a protein called tau. But drug discovery has focused almost entirely on trying to reverse the symptoms of Alzheimer’s by getting rid of amyloid plaques.

In the new research article, mice that had been given a form of Alzheimer’s disease showed damage inside neurons of the brain which occurred prior to the formation of amyloid-containing plaques. It was thought that damage in Alzheimer’s disease is due to amyloid plaque buildup outside of neurons, but this study shows that damage within neurons happens even before those signs show up. Though the research was conducted in mice (which does not capture all the aspects of human Alzheimer’s disease), it lends support to the need for studying other mechanisms of Alzheimer’s disease progression.

In short, researchers have taken for granted that amyloid plaques are a cause of Alzheimer’s disease because the two are linked, but it's possible that they are a consequence of disease progression in certain cases or even coincidental. This would explain why aducanumab a drug which targets amyloid which was approved last year for Alzheimer’s disease by the US Food and Drug Administration, has failed to show clinical benefit in two trials.

The single-minded focus on one theory to the exclusion of others has arguably stymied the development of Alzheimer’s disease drugs. Over the past three decades, hundreds of candidate drugs that target the accumulation of amyloid have failed to prevent the memory loss and cognitive decline that harm Alzheimer’s disease.

How did researchers get focused on one theory of how Alzheimer’s disease develops to the exclusion of others? In his brilliant new book, How Not to Study a Disease, noted neurobiologist Karl Herrup exposes how the problems of the field can be traced back to the first case which was described based on its pathological features (plaques and tangles). But Herrup also found after asking different physicians that there’s no single definition that covers the entire range of clinical cases. Each physician focuses on a different aspect of the disease.

As Herrup notes, “Alzheimer’s disease was to be defined by the presence of plaques. Yet plaques are a feature that is not present in 15 per cent of the people with a clinical diagnosis of Alzheimer’s, and a feature that is present in people of all ages including 30 per cent of elderly people without any cognitive impairment. If this doesn’t make sense to you, it’s because it doesn’t make sense.”

Or in other words, a significant number of people who have been diagnosed with Alzheimer’s don’t have the plaques (that were supposed to be the landmark characteristic) and around a third of elderly adults have plaques without having Alzheimer’s. This loose association did not deter those researchers who declared that anyone with plaques had “preclinical” Alzheimer’s disease even though they had no symptoms.

But there is another problem with trying to explain plaques as the sole cause of Alzheimer’s disease. There is only a weak link between plaque burden and the severity of disease symptoms.

Despite these criticisms and some spectacular drug failures, the amyloid hypothesis isn’t dead. Right now, other drugs that target the pathway for the accumulation of amyloid are in the pipeline. And hopefully one of these will fare better for at least a subset of patients.

Some researchers believe that drugs that target amyloid are being administered too late when irreversible damage has already been done. We need to treat people with preclinical Alzheimer’s disease.

But we cannot afford to continue to put all of our eggs in one basket. It’s clear that other research avenues need to be investigated. What we need is accelerated research on other disease targets. Tau, the protein responsible for tangles is one such target that deserves more attention.

Then there’s also an alternate theory that infections might play a part in Alzheimer’s disease. Last year, in a column I mentioned a long COVID condition in elderly patients that had been dubbed “Alzheimer’s-like syndrome” by researchers. For decades there has been mounting evidence that some pathogens might be involved in at least some cases of Alzheimer’s disease. But this theory was considered fringe. Now, it is finally being seriously considered by the wider Alzheimer’s disease field.

Anirban Mahapatra is a scientist by training and the author of a book on COVID-19. He’s writing a second popular-science book

The views expressed are personal

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