Alzheimer’s as an autoimmune disease: ‘We will need competence in the area of immunology’
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What if Alzheimer’s disease, a neurological disorder that has confounded researchers since its identification in 1907, were not a brain disorder at all? What if it were instead an autoimmune disease that attacks the brain?
That is the idea proposed in a recent paper published in Alzheimer’s & Dementia by Donald F. Weaver MD, PhD, senior scientist with the Krembil Brain Institute and professor of chemistry, medicine and pharmaceutical science at the University of Toronto. In that paper, Weaver suggests a new mechanistic model of Alzheimer’s disease, the most common form of dementia worldwide, as a disease of the immune system within the brain.
“Ever since Alzheimer’s disease was first described in 1907, the focus has been on two proteins: one called beta amyloid and one called tau,” Weaver told Healio. “The focus was that these two proteins were abnormally produced in the brain, and then they aggregate. When they aggregate, they become toxic.
“That has been the overwhelming conceptualization of Alzheimer’s disease for decades now,” he added. “Although there is an overwhelming amount of experimental data to support it, the problem has been that multiple attempts to devise therapies and drugs that target this protein production have all failed. In the Alzheimer’s world, you often hear, ‘The amyloid hypothesis is dead, we need new thinking.’ That has been the dominant undercurrent over the last several years.”
Weaver’s group conducted a comprehensive search of peer-reviewed and patient-facing literature to create the model.
From their observations, it is suggested that pathogen- or damage-associated molecular pattern-stimulating events, such as infection, trauma, ischemia or pollution, causes the release of amyloid-beta as a physiological immunopeptide. This response, in turn, triggers a cytokine-based innate immune cascade, wherein amyloid beta demonstrates immunomodulatory/antimicrobial duality, according to the findings.
Weaver suggested that the antimicrobial properties of amyloid beta cause the protein to attack not only the bacterial cells, but neurons as well. This occurs because neurons and bacteria have “electrophysiological similarities,” Weaver posited.
Moreover, further release of amyloid beta yields a self-perpetuating cycle of this attack.
“[Autoimmune disease] includes [amyloid beta] as an important molecular player, but rejects the “amyloid hypothesis,” recognizing [amyloid beta] as a physiologically oligomerizing cytokine and part of a larger immunopathic conceptualization of [Alzheimer’s disease],” he wrote in the paper.
The findings could have a profound impact on patient care, given that more than 50 million individuals worldwide live with Alzheimer’s disease in the absence of accurate diagnostics or effective therapeutics.
Healio sat down with Weaver to discuss the long-standing theories of disease pathogenesis and how his findings could usher in a new way of thinking on the condition.
Healio: Is it possible that the amyloid hypothesis is correct, but we have just not been able to produce the right drugs that hit the target the right way? Or have we reached the end of the line with this approach?
Weaver: That is probably the largest question right now in Alzheimer’s research. There is the amyloid camp that says it is still valid, we just have not got the agent yet. But the other camp says, “Come on. We have had many drugs that worked quite well in test models that ultimately failed.” This debate is an area of ongoing controversy.
Healio: Do you believe that your hypothesis will effectively lead to a cure for Alzheimer’s disease?
Weaver: It is perhaps a bit naïve to think that will be one magic bullet that will be sufficient. This is too complicated a disease. More likely is that we will ultimately need multiple medications with multiple mechanisms of action.
Healio: What is your new paradigm proposing?
Weaver: The background to this is that if we go back to 1907 when Dr. Alzheimer first described the disease in his initial case, even he said that other cells are present that seem to be related to inflammation. Specifically, they are microglial cells that we now know are in the immune system. It has been playing a central role in Alzheimer’s since the beginning.
If one looks at various risk factors for the disease, we can see repetitive head trauma, dental infections with bacteria, air pollution, among others. This is a wide variety of factors that are all so, so different. But when you dig deeper into the research, you see involvement of the immune system as a common thread.
Healio: How does this relate to beta amyloid?
Weaver: Beta amyloid is supposed to be in your brain. It is not abnormally produced. It is, in fact, being normally produced as part of the immune system in the brain. So, we created a computer simulation showing that beta amyloid can lay on the surface of bacteria and puncture holes in them. However, we also showed that beta amyloid can puncture holes in neurons.
The crux of our argument is that something triggers the immune system that makes beta amyloid turn on and begin to seek and destroy bacteria. But the beta amyloid can’t differentiate the bacteria from the neurons, so it starts to kill them as well. Thus, the processes of Alzheimer’s begin.
Healio: Were you surprised at your findings?
Weaver: We sure were. As a person who has dutifully plugged away with the amyloid and tau story for the last 25 years, it has been interesting having all these pieces fall together. It has been surprising but gratifying.
Healio: Could you talk about the response to your findings from the clinical, research and patient communities?
Weaver: It varies from, “Wow, this is really neat,” to “You have to be kidding me.” There are a lot of researchers in the area of Alzheimer’s who are passionately wed to their own way of thinking — with, I might add, lots of research funding to support it. So, there are other theories out there. What I would like to think is that this is a valid hypothesis that we are putting forward. This is worthy of additional study and can take a valued place among new and old theories.
Healio: Should rheumatologists start thinking more about Alzheimer’s?
Weaver: The research institute in which I work here in Toronto has three main threads: the brain, rheumatology and ophthalmology. We work side-by-side with rheumatologists all the time. I have found it incredibly useful to go talk to them because their thinking about the immune system is much more developed and advanced than ours in neurology. We appreciate the expertise they bring to the table in our patients.
The other thing that is relevant is that we are starting to use biologics more and more in the area of neurology. Certainly, at our own institution, rheumatologists are the best people to administer those drugs. They are experienced at suppressing the immune system. So, I see a lot of potential overlap between the two specialties.
Healio: Will there be clinical trials of your approach in patients?
Weaver: At this point, I would like to draw a distinction between the autoimmune diseases that rheumatologists deal with and the type of autoimmune disease that has been put forward for Alzheimer’s. For rheumatoid arthritis or lupus, it is at the level of adaptive immunity. This model of Alzheimer’s is a model of innate immunity. In that regard it is different.
So, with that in mind, what we have proposed is that amyloid beta has an immunomodulatory influence on the triggering receptor expressed on myeloid cells 2 (TREM2)-glycosaminoglycan (GAG)-Nod-like receptor protein 3 (NLRP3) network, and the L-tryptophan and L-arginine metabolism. What we are hoping is that this focus will lead to new diagnostics and therapeutics.
Healio: Should rheumatologists be part of the care team for patients?
Weaver: I like to think that Alzheimer’s care will ultimately require a team approach that includes a focus on the immune system. We will need competence in area of immunology. Given the experience and expertise rheumatologists have with the immune system, I think they would be an excellent member of the care team for any Alzheimer’s patient.
Healio: What could this change for Alzheimer’s patients?
Weaver: Because we lack diagnostics and therapeutics, if someone comes in with a memory disorder, we do mental status tests, memorization tests, other such interventions. Coming up with a concrete mechanistic explanation for the disease can lead to new diagnostics and therapeutics. It can lead to a pipeline. Hopefully, that will lead to meaningful change for these patients. This is a complicated disease.
Reference:
Weaver DF. Alz & Dem. 2022;doi:10.1002/alz.12789.
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