Rethinking Alzheimer’s: Is It an Autoimmune Disease and Not Just a Disease of the Brain?
Are we going to do something different with Alzheimer’s if we classify it as an autoimmune disease instead of a neurological disorder? Why or why not?
How does the shift in thinking of beta-amyloid as a potentially protective response as opposed to simply an injury in the brain, change the traditional ways in which we conceptualize
Alzheimer’s, the ways neuroscientists develop new medications, and the sense of urgency there has been to fund research into potential medications?
In thinking about different ways of thinking about Alzheimer’s (like mitochondrial dysfunction, infection, or metal toxicity, etc.), ramifications will extend past science and cognition. What des the exploration of alternative models of Alzheimer’s mean for the future of scientific research and healthcare policy?
Think seriously about the above questions and pick one or more to expand into a lengthier paper. Your paper should reflect on ways in which the scientific understanding of the nature of the Alzheimer’s disease is changing, tap into different models of brain potential-shift from neurological to autoimmune models that can be quite different from how we form our conceptual thinking about the science of Alzheimer’s disease, and the potential implications for medicine, public health and society. Use the findings and reasoning from the text and, if you’re able, support it with your own interests and research. This is your chance to think critically about how changing our framing of a disease can change everything, from where we put research money to the treatment of the patient with the disease diagnosis or mismatch.
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Rethinking Alzheimer’s: Is It an Autoimmune Disease and Not Just a Disease of the Brain?
Introduction: We Are Seeing the Depths of Our Misunderstanding of Brain Science
Alzheimer’s Disease has long been classified as a neurodegenerative disease – a slow, irreversible deteriorating process characterized by the progressive loss of memory, thinking, and reasoning skills. There are over 50 million people worldwide with this disease and a new case is diagnosed every three seconds. While this is a medical issue, it is also a global health crisis. The personal costs are staggering – people forget their own names, children, or lifelong partners. The economic costs are even more staggering; what was once thought to be healthcare system costs for long-term care, will soon be a growing financial thermonuclear bomb.
Despite an exceptional amount of research-oriented investment (and by investment I mean the billions of dollars spent and consumed by scientists, researchers, and educators), an effective intervention/cure for this disease has not materialized. The overwhelming proportion of treatments that actually are approved, only slow the progression of the symptoms instead of addressing the condition itself or reversing its progression. This unbearable stagnation evokes the question – are we even addressing the correct cause?
Dr. Donald Weaver, neuroscientist and physician at Toronto’s Krembil Brain Institute, has asked himself that very question. After 30 years of research, he and his research team are proposing a new paradigm! Alzheimer’s is not primarily a disorder of the brain; it’s an autoimmune disease whereby the brain immune system intentionally destroys, attacks and targets its own neurons.
The Beta-Amyloid Controversy: A Scientific Obsession Gone Awry
Research specific to Alzheimer’s has put an obsession on one molecule, beta-amyloid, for the last three or more decades. The sticky protein fragment creates plaques around cells in the brain, and is considered a classic symptom of the disease. Weak molecular neurotoxic buildup of beta-amyloid causing the death of brain cells, resulting in cognitive decline.
This controversy, the amyloid cascade hypothesis has created waves in research, drug development, cultural meaning and pharmaceutical politics since it came to the fore in the 1990’s. But besides all the praise there are a few cracks to the theory that have begun to show.
One significant egregious example, may be a study in 2006 that has appeared in citations thousands of times since then, and in Science magazine 2022, suggested that the published study was based on altered images, and fabricated findings.
In 2021 the FDA though controversially, approved aducanumab, essentially one of the first drugs designed to remove brain beta-amyloid plaques albeit the critics stated the evidence to approve was partial, neither consistent, and claimed cognitive improvements were small with episodic hair raising risks.
Decades of funding, research, and discussion on beta-amyloid evidence have relied on incomplete reports evidencing some not working effects, and researchers now believe that the field is in an “intellectual rut” pouring time and resources into what many researchers suggest is a flawed model and may be easily ignoring a number of other alternatives creating possibilities with best results.
A Paradigm Shift: Einstein's Work Brings Us into a New Understanding of Alzheimer's Disease
Dr. Weaver then offers us a completely new interpretation: it’s not that beta-amyloid is bad, beta-amyloid is part of the brain’s own immune system.
The immune system is a part of every organ of the body including the brain. The immune system is made up of special cells and molecules that work together to ward off infection, heal trauma, and restore equilibrium. The assembled immune response is worried about protecting you and ensuring homeostasis; that’s what Weaver’s lab is arguing: beta-amyloid is, in-fact, a protective molecule that the brain produces when it has something minor to contend with (such as a traumatic brain injury or when an unknown infection invades), beta-amyloid serves as a protective response at a local level.
Why does this go wrong?
Because the membranes that wrap up bacteria are very similar to our own sophisticated human brain cell membranes.
Beta-amyloid is programmed to recognize and instigate attacks for dangerous invaders without differentiating between what is foreign (something or someone that shouldn’t be there) or the brain’s neurons.
Hence confusion leads to an uncontrolled attack by the immune system. This immune failure is simply misapplying an immune response, or autoimmunity.
Over time, an immune attack leads to chronic inflammation, ongoing destruction of human brain cells, and chronic effects associated with Alzheimer’s Disease such as memory loss, confusion, and erratic behavior.
This emerging model classifies Alzheimer’s as an autoimmune disorder—where the immune response mechanically is appropriate yet self-destructive (where the body’s own immune response is self-inflicted-negative symptoms and disease). In essence, the final shift of naming Alzheimer’s isn’t a multi-cell disease of aging that decays, but rather that Alzheimer’s is an immune system malfunction that defeats itself.
Why Existing Autoimmune Therapies Don’t Work Alzheimer’s
Autoimmune pathology such as rheumatoid arthritis, lupus, and multiple sclerosis are commonly treated with immunosuppression therapies such as corticosteroids or monoclonal antibodies that inhibit the inappropriate activity of this overactive immune system by treatment which can have a profound impact on patients’ quality of life.
But those immunosuppressive therapies have little to no impact on treatment of Alzheimer’s and here are the reasons:
The brain is a unique organ and is considered “immune privileged” and has a different immune environment than the rest of the body.
The immune cells of the brain, which are mostly the microglia, react differently to the environmental threats, and also have their activity tightly controlled by the blood-brain barrier, and in totality are in a different milieu entirely.
Immune therapies that have been developed to target the periphery do not cross the blood-brain barrier, nor would they function in the brain’s unique environment.
Dr. Weaver explained, to find a solution to Alzheimer’s, a whole new class of drugs needs to be developed specific for modulation of the immune system in the brain and in the central nervous system.
Exploring Other New Theories of Alzheimer’s
In addition to the autoimmune hypothesis, there are multiple other new theories being proposed that are now being explored, each of which offers a different view of what may be driving Alzheimer’s disease:
- Mitochondrial Dysfunction
Mitochondria are the energy factories of the cell and they convert oxygen and glucose into ATP that powers every action conducted in the body (thinking and memory included).
Some researchers suggest that in Alzheimer’s:
- Mitochondria deteriorate and are unable to convert oxygen and glucose producing an adequate amount of energy.
- The lack of energy leads to cellular exhaustion and death, especially in areas of the brain that have high levels of function, like the hippocampus (where new memories are created).
- Infectious Agents
Another theory involved the possibility that chronic infections could trigger the development of Alzheimer’s, for example oral bacteria associated with gum disease (Porphyromonas gingivalis):
The bacteria could cross the dentition into the bloodstream to the brain:
Where the bacteria could generate an immune response that leads to beta-amyloid production and inflammation.
- Metal Toxicity
In addition, there have been suggestions made about roles of essential metal imbalances such as copper, zinc, and iron.
- An excess of iron may accelerate the production of free radicals that produce damage to neurons.
- Poor metal regulation could, directly or indirectly, interfere with enzyme activity and result in oxidative stress damage that underpins neurodegeneration.
- Each of these theories (some of which you may know as models of Alzheimer’ s disease) also have potential markers for exploratory purposes, new targets for new therapeutic intervention and new ways of researching along with the autoimmune hypothesis.
The High Stakes: A Global Health Emergency
The implications of failing to develop effective treatments for Alzheimer’s are profound:
– With lifespans increasing, more and more individuals are living long enough to develop dementia-related disorders.
– The economic impact is extreme: On the global stage, the economic impact of dementia is utterly staggering – the World Health Organization estimated the global cost of dementia to be $1.3 trillion in 2020 and to exceed $2 trillion by 2030.
– Caregivers – most often family members – experienced emotional, physical, and financial distress, often sacrificing career and mental wellness to care for family and loved ones.
– And then there is the human experience, where it is extremely sad that a formerly engaged individual may no longer recognize a spouse, or their children, no longer speak or eat, and the very individual they loved slowly fades in front of everyone who loves them.
For these reasons, new ideas, and bold new thinking are not negotiable; they are necessary.
Conclusion: A New Direction in Alzheimer’s Research
Dr. Weaver’s autoimmune hypothesis provides a new avenue in the battle against Alzheimer’s, and, not just a new perspective, but it is an entirely new paradigm, rejecting an entrenched way of thinking, ushering in the era of precision brain immunology as a new way to treat the brain. This new way, allows for treatments that target a person’s immune response to the brain rather than eliminating one “bad” protein.
By replacing “plaque buildup” with the notion of “immune misfire”, we are gaining a broader and more trusted understanding of this complicated disease. Moreover, we are validating interdisciplinary approaches, especially in the intersectionality of immunology and neuroscience, and microbiology and dental science management of a multifactorial disease like Alzheimer’s.
Final Thought: It is Time for New Questions
A Pivotal Shift in Outlook: From Elimination to Contribution
For much too long, the question driving Alzheimer’s research has been:
“How do we remove beta-amyloid?”.
This focus has standardized decades of research, clinical trials, and drug discovery efforts, and led to spending (wasting) billions of dollars trying to remove beta-amyloid plaques from the brain—not as a means to achieve health (whereupon beta-amyloid is possible a useful, native, innate product) but rather as an obstruction (a toxic byproduct, a pathological miscalculation, or even the single causation for neurodegeneration).
However, despite the billions poured into “disrupting” the plaque, we do not have a cure, and in most instances we have not altered the progress of Alzheimer’s disease. Failure of amyloid-clearing drugs, public controversies over data-reporting honesty, and controversial regulatory approvals such as Aducanumab, have all helped build chronic skepticism related to the entirely unfulfilled claims of the amyloid hypothesis. And now a key question emerges:
“What if beta-amyloid is not the problem? What if it is an unintended—but useful—response?” “And why is beta-amyloid even there?”
Asking “why?” instead of “how do we remove it?” shifts the conversation and allows us to rationalize that beta-amyloid is not an invading (or a miscomprehended) protein, but rather a native molecule that plays a role in the brain’s innate immunity to injury, as it acts to allow for a balancing effort through the stress or the injury or perhaps even towards an infection. Perhaps beta-amyloid was never intended to be removed, and we were meant to understand it instead.
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