Alzheimer’s may not be primarily a brain disease. A new theory suggests it’s an autoimmune disease.

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THE CONVERSATION

This article was originally published on The Conversation, an independent and not-for-profit source for news, analysis, and commentary from academic experts. Disclosure information is available on the original website.

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Author: Donald Weaver, Professor of Chemistry and Director of the Krembil Research Institute, University Health Network, University of Toronto

The quest for a cure for Alzheimer’s disease is becoming an increasingly competitive and controversial endeavor, with several major controversies taking place in recent years.

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In July 2022, Science Magazine reported that a key 2006 research paper, published in the prestigious journal Nature, which identified a subtype of brain protein called beta-amyloid as the cause of Alzheimer’s, may have been based on falsified data.

A year earlier, in June 2021, the U.S. Food and Drug Administration approved aducanumab, an anti-antibody beta-amyloid, for the treatment of Alzheimer’s, although data to support its use were incomplete and conflicting. Some doctors believe aducanumab should never have been approved, while others believe it should be given a chance.

With millions of people in need of effective treatment, why are researchers still fumbling to find a cure for arguably one of humanity’s most important diseases?

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Escape the amyloid beta rut

For years, scientists have focused on developing new treatments for Alzheimer’s by preventing the formation of brain-damaging clumps of this mysterious protein called beta-amyloid. In fact, we scientists seem to have gotten into a kind of intellectual rut, focusing almost exclusively on this approach and often neglecting or even ignoring other possible explanations.

Unfortunately, this commitment to studying the abnormal protein clumps has not translated into a useful drug or therapy. The need for a new “out of the box” way of thinking about Alzheimer’s is emerging as a top priority in brain research.

My lab at the Krembil Brain Institute, part of the University Health Network in Toronto, is developing a new theory of Alzheimer’s disease. Based on our 30 years of research, we no longer view Alzheimer’s primarily as a brain disease. Rather, we believe that Alzheimer’s is primarily a disorder of the immune system in the brain.

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Found in every organ in the body, the immune system is a collection of cells and molecules that work in harmony to repair injuries and protect against foreign invaders. When a person stumbles and falls, the immune system helps repair the damaged tissue. When someone contracts a viral or bacterial infection, the immune system helps fight these microbial invaders.

Exactly the same processes take place in the brain. When head trauma occurs, the brain’s immune system kicks in to help repair it. When bacteria are present in the brain, the immune system is there to fight back.

Alzheimer’s as an autoimmune disease

We believe that amyloid beta is not an abnormally produced protein but a normally occurring molecule that is part of the brain’s immune system. It’s supposed to be there. When brain trauma occurs or when bacteria are present in the brain, amyloid beta is a key contributor to the brain’s overall immune response. And here the problem begins.

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Because of striking similarities between the fat molecules that make up both the membranes of bacteria and the membranes of brain cells, beta-amyloid cannot distinguish between invading bacteria and host brain cells, and mistakenly attacks the very brain cells it’s thought to protect.

This leads to a chronic, progressive loss of brain cell function, eventually culminating in dementia – all because our body’s immune system cannot distinguish between bacteria and brain cells.

Viewing Alzheimer’s disease as a misguided attack by the brain’s immune system on the very organ it’s supposed to be defending turns out to be an autoimmune disease. There are many types of autoimmune diseases such as B. rheumatoid arthritis, in which autoantibodies play a crucial role in the development of the disease and in which steroid-based therapies can be effective. But these therapies are not effective against Alzheimer’s disease.

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The brain is a very special and distinctive organ considered to be the most complex structure in the universe. In our Alzheimer’s model, amyloid beta helps protect and strengthen our immune system, but unfortunately it also plays a central role in the autoimmune process that we believe can lead to the development of Alzheimer’s.

Although drugs traditionally used to treat autoimmune diseases may not be effective against Alzheimer’s disease, we strongly believe that targeting other immune-regulating signaling pathways in the brain will lead us to new and effective approaches to treating the disease.

Other theories of the disease

In addition to this autoimmune theory of Alzheimer’s disease, many other new and different theories are emerging. For example, some scientists believe that Alzheimer’s is a disease of tiny cellular structures called mitochondria — the energy factories in every brain cell. Mitochondria convert oxygen from the air we breathe and glucose from the food we eat into the energy needed to remember and think.

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Some claim it’s the end result of a specific brain infection, with bacteria from the mouth often suspected as the culprit. Still others suggest that the disease may result from the brain’s abnormal handling of metals, possibly zinc, copper or iron.

It’s gratifying to see new thinking on this age-old disease. Dementia currently affects more than 50 million people worldwide, with a new diagnosis being made every three seconds. People with Alzheimer’s disease are often unable to recognize their own children or even their 50+ spouse.

Alzheimer’s is a public health crisis that needs innovative ideas and new directions. For the well-being of people and families living with dementia, and for the socioeconomic impact on our already stressed healthcare system as we cope with the ever-increasing costs and demands of dementia, we need a better understanding of Alzheimer’s, its causes, and what we can do to treat it and help the people and families who live with it.

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Donald Weaver receives financial support from the Canadian Institutes of Health Research and the Krembil Foundation.

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