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The Case for Treating Alzheimer’s Like an Autoimmune Disease

By Simon Spichak, MSc | October 19th, 2022

Donald Weaver, a researcher and physician who acts as co-director at the Krembil Brain Institute, provides evidence that Alzheimer’s is a result of the brain’s immune system misfiring — opening up avenues for new treatments.

One of the most anxiety-inducing aspects of an Alzheimer’s diagnosis is the loss of control associated with the disease as it progresses. At the moment, there is no way to cure or reverse Alzheimer’s, and developing treatments for it has proven to be one of modern medicine’s greatest challenges: So far, 99 percent of drugs tested to treat the disease have failed

Because the cause of the disease is still being determined, ultimately, some number of dozens of pharmaceutical companies will have inevitably been spinning their wheels focusing on the wrong targets. One of the most popular focuses so far has been on clearing the amyloid protein plaques that tend to build up in the brains of people with Alzheimer’s.

Donald Weaver, a researcher and physician acting as the co-director of the Krembil Institute, believes there’s substantial evidence that while amyloid plays a role in the Alzheimer’s story, it isn’t the main character. Instead, Weaver believes that Alzheimer’s may be the result of the brain’s immune system reeling out of control.

“We don’t think of Alzheimer’s as fundamentally a disease of the brain,” Weaver recently stated in a press release. “We think of it as a disease of the immune system within the brain.”

Weaver authored a recent perspective paper in the journal Alzheimer’s and Dementia explaining the evidence for his hypothesis — and pointing to hopeful new avenues of research. 

Laying out a new model of Alzheimer’s disease

“We need new ways of thinking about this disease, and we need them now,” said Weaver. “To date, most of the approaches in Alzheimer’s research have been based upon the theory that a protein called beta-amyloid, which is supposedly abnormal in the brain, clumps up. And when it clumps up, it kills brain cells.” 

He believes that beta-amyloid is actually functioning as intended — an important part of the immune system. When infections or other biological and environmental factors — air pollution, stroke, depression, trauma — damage the brain, its immune system mounts a response. Beta-amyloid is released in the brain as an immune response to limit the damage and flag nearby immune cells to clean it up. 

This idea is supported by the properties of the beta-amyloid protein itself: It activates the brain’s microglia leading to the release of proteins called cytokines which kill off damaged brain cells. In addition, beta-amyloid itself acts as an antimicrobial agent that literally rips apart bacteria. This property unfortunately can also damage neurons when the immune system of the brain misfires. It leads to the release of more inflammatory proteins and more beta-amyloid, leading to the characteristic symptoms of Alzheimer’s.

Weaver lays out a roadmap for testing these ideas. Rather than looking for specific pathogens that cause Alzheimer’s, he suggests broadly looking at how beta-amyloid may lead to inflammation in the brain. Next, scientists would need to figure out exactly how beta-amyloid stimulates the brain’s immune cells. It is also important to connect the autoimmune dysfunction of these immune cells to the overall brain pathology seen in Alzheimer’s patients: Damage to healthy connections in the brain and the deposition of tau tangles. 

Taking back control of the brain’s immune system

Two signaling molecules within the brain regulate its immune system — L-tryptophan and L-arginine. Simply put, these are signals that can tamper down the immune response and also prevent further accumulation of beta-amyloid plaques. Low levels of L-tryptophan are also associated with cognitive dysfunction in Alzheimer’s disease. These molecules are key ingredients for other important signals within the brain — like flour and eggs are key for many different baked goods. 

It is the first step of an important biological recipe responsible for creating many different end-products called metabolites. Think about how flour and eggs are used for baking cakes (both the delicious and the terrible ones). L-tryptophan is part of recipes that produce both neuroprotective and neurotoxic molecules, and even the building block for neurotransmitters. 

Gerard Clarke, a principal investigator at APC Microbiome Ireland who studies tryptophan, spoke with Being Patient about how this molecule is transformed into different biological signals throughout the body. “There is a pretty complex conversation going on between the metabolites [(molecules derived from)] of tryptophan and the immune system,” he said. But the connection between tryptophan levels and cognitive dysfunction isn’t so simple. When tryptophan is transformed into quinolinic acid by the brain’s immune cells, the microglia, it could contribute to neuronal damage in Alzheimer’s disease. If someone already has some inflammation in the brain, he suggests that “increasing tryptophan levels might just be adding more fuel to the fire.” 

However, Clarke agrees that developing drugs that affect the processing of tryptophan could help reduce inflammation in the brain. Basically, these drugs would dictate which recipes tryptophan should be used for. Treatments based on this model might involve specific receptors that detect tryptophan in the brain or changing the gut microbiome composition, or increasing the levels of tryptophan produced by the microbiome while preventing it from being turned into toxic molecules. However, all of these new avenues of treatment will need to be validated through clinical trials.

“We are very excited in our lab,” said Weaver. “We think that this autoimmune theory is sound and represents a significant conceptual step forward.”  

 

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