What causes Alzheimer’s disease?

Exploring the brain immune system malfunctioning hypothesis.

Scientist studies brain images

For the past 30-40 years, Alzheimer’s disease research has been dominated by a proposal called the “amyloid hypothesis”.

According to this hypothesis, Alzheimer’s disease is caused by a protein in the brain called beta-amyloid which clumps into small aggregates that are toxic to brain cells, ultimately killing them and leading to the symptoms of dementia as these brain cells die.

Also according to this hypothesis, beta-amyloid is an abnormal protein that is not supposed to be in the brain, but is abnormally produced for reasons that are not fully understood.

Photo: Canva

Regrettably, almost all drugs developed to block the production of beta-amyloid and its aggregation have failed to help treat the disease. Recently, there has been some limited success with two therapeutics, one called lecanemab, the other called donanemab, which bind to beta-amyloid clumps and which seem to have some effectiveness in treating the disease.

The partial success of these two agents supports the notion that beta-amyloid probably plays an important role in the progression of Alzheimer’s disease, but that the amyloid hypothesis is not sufficient to explain the full cause of Alzheimer’s.

In short, the amyloid hypothesis is part of the answer, but isn’t the whole answer.

One of the emerging leading hypotheses is that Alzheimer’s is caused by malfunctioning of the immune system within the brain, which in turn leads to inflammation in the brain with subsequent brain damage.

– Dr. Donald Weaver

In the search for additional or alternative explanations for Alzheimer’s, many other suggestions and hypotheses have been put forth. These include proposals that Alzheimer’s arises from slow infections of the brain, inflammation of the brain, damage to brain cell membranes, too much copper (or zinc, or iron) in the brain, and so on – the list is long with many different and varied suggestions.

One of the emerging leading hypotheses is that Alzheimer’s is caused by malfunctioning of the immune system within the brain, which in turn leads to inflammation in the brain with subsequent brain damage.

In our lab, we are studying this brain immune system malfunctioning hypothesis. Using state of the art computer modelling methods, we have been simulating the behaviour of beta-amyloid when it is near a brain cell.  These simulations predict that the beta-amyloid protein initially sticks to the surface of a brain cell and then part of the protein then wiggles through the brain cell’s membrane, rupturing it and causing the cell to die.

We also noticed that beta-amyloid protein does the exact same thing to bacterial cells.  Additional extensive computer modelling also suggested that beta-amyloid is in fact a normally occurring protein in the brain and functions as a type of molecule called a “cytokine”, where cytokines are messengers that carry information between immune cells in the brain.

Based upon these computer simulations, backed up by experiments using brain cells, we have devised a new theory of Alzheimer’s disease: following a variety of stimuli, including brain infections, trauma, or even depression, beta-amyloid is released as a cytokine which is trying to protect the brain. As part of its protection duties, beta-amyloid searches for bacteria in the brain, primed to kill the bacteria should any be detected. However, in a horrible case of mistaken identity, beta-amyloid gets confused and misrecognizes normal brain cells as bacteria, leading to the death of these brain cells.

In this way, Alzheimer’s disease emerges as a disorder of the brain’s immune system, which occurs because beta-amyloid, while trying to defend the brain, cannot differentiate between bacteria and brain cells, culminating in the accidental death of brain cells.

scientist looking at brain images

Photo: Canva

We are now exploiting this new and interesting theory of Alzheimer’s disease in an attempt to identify potential new drugs for the treatment of this chronic, progressive brain disease.

The brain is the most complex organ in the human body, and arguably, Alzheimer’s is one of the most complicated diseases of the brain. We need new and innovative ways of looking at this disease in our attempt to devise new therapies. The notion that Alzheimer’s occurs because beta-amyloid, as an important contributor to the brain’s immune system, gets confused and mistakes brain cells for bacteria is a new way to look at this challenging disease.

Time and additional research will tell us if this theory is right or wrong, but when it comes to Alzheimer’s, all new knowledge is useful. 

ABOUT THE AUTHOR

Dr. Weaver is a Senior Scientist at the Krembil Research Institute at the University Health Network. He is a professor of Chemistry, Medicine and Pharmaceutical Science at the University of Toronto and a neurologist at the Toronto Western Hospital.

Dr. Weaver is also the Krembil Chair in Drug Discovery for Alzheimer’s Disease, Chief Medical Officer of Treventis Corporation, and is the former President of Epilepsy Canada.

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