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Donald Weaver from UHN’s Krembil Brain Institute in his Toronto lab on June 17, 2022.JENNIFER ROBERTS/The Globe and Mail

Alzheimer’s disease is traditionally understood to be caused by the accumulation of abnormal protein in the brain. Get rid of the protein, the thinking goes, and you reduce the harm.

But what if Alzheimer’s disease is actually an autoimmune disease?

For more than 20 years, Toronto neurologist and medicinal chemist Donald Weaver has been pursuing a different explanation for the neurodegenerative disease in the hope of finding new ways to treat and prevent it. His unconventional hypothesis has now won him a major award.

Dr. Weaver will be awarded Wednesday the silver Oskar Fischer Prize, worth US$400,000. The prize, granted through the University of Texas at San Antonio (UTSA), is given to researchers to expand the understanding of Alzheimer’s disease, which has long confounded those seeking a cure.

“What this gives us is external validation and external support and belief that our approach has value, and indeed, may have value leading to alternative therapeutic directions for Alzheimer’s disease,” says Dr. Weaver, director of the Krembil Brain Institute at Toronto’s University Health Network.

More than 115 years since the first patient was documented, the causes of Alzheimer’s disease are still not well understood. For years, the dominant hypothesis has been the amyloid hypothesis – that the main cause is a build-up of beta amyloid, which are sticky protein fragments that form toxic clumps or plaques. However, amid the failures of multiple drugs that target amyloid, the call to explore alternative explanations of the disease has grown louder. Most recently, Genentech, part of the Roche Group, announced this month that its trial of the anti-amyloid drug crenezumab did not produce a statistically significant clinical benefit.

Instead of viewing beta amyloid as an unwanted protein, Dr. Weaver suggests it is actually a normal part of the innate immune system in the brain, and plays a number of roles, including as a messenger and as a bacteria-killer. Anything that produces an immune response, whether it’s an infection, trauma or exposure to noxious substances, triggers cells in the brain to release beta amyloid, he explains.

The problem occurs when beta amyloid mistakes healthy brain cells for bacteria, he says. “The end result is that it – oops! – accidentally starts killing brain cells.”

The damage doesn’t end there, he explains. Fragments that are created when beta amyloid destroys brain cells go on to trigger the continued release of beta amyloid, which, in turn, can mistakenly kill more brain cells, he says. “This is how it ultimately becomes a chronic disease over the course of many, many, many years.”

Dr. Weaver says genetics may play a role in determining why some individuals develop Alzheimer’s disease but other’s don’t, as the former may produce larger quantities of beta amyloid in response to the same immune system triggers. But he says there’s an argument that everyone would eventually develop Alzheimer’s disease if they were to live long enough. Biological variability may account for why it progresses more rapidly in some than others, he suggests.

Building on his hypothesis, Dr. Weaver believes it’s possible to tackle Alzheimer’s disease by exploiting the body’s natural way of controlling the immune system. He and his team have screened roughly 1,300 chemicals in the brain for their ability to suppress the innate immune system, and have identified certain chemicals they believe could be developed as possible therapeutics.

His hypothesis may also have implications for the prevention of Alzheimer’s disease, he adds.

“If we accept the fact that Alzheimer’s disease is an immune-based disease that has certain triggers, then I think that we need to go back and revisit the risk factors,” he says. For instance, he points to the need to better understand how different types of air pollution affect the brain, and to find ways of preventing head trauma.

The same immune system mechanism may also apply to other diseases, such as Parkinson’s disease or other forms of dementia, Dr. Weaver says. “This is a broad conceptual basis which can be extrapolated to other disorders.”

Any of the explanations for the disease proposed by the 10 winners of this year’s Oskar Fischer Prize may end up being right or wrong, says Jenny Hsieh, director of the UTSA Brain Consortium. But the key is to provide researchers the opportunity to pursue ideas that are outside the box, she says. “We just need people to be able to work on different ideas, and be inclusive of that, because the bottom line is all of the current approaches to Alzheimer’s disease [are] not working.”

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