Autoimmune disease theory and other hypotheses

Also this year, the observance of World Alzheimer’s Day – celebrated on September 21 – was an opportunity for information, discussion and hope, both for patients with the disease, as well as for those who care for them and researchers. Alzheimer’s disease is the most common form of dementia. It occurs more frequently after age 65 and affects women more often. Like all forms of dementia, it involves a gradual deterioration in cognitive functions, beginning with memory. It is no coincidence that Alzheimer’s disease is called the “disease of the century”: in the world currently, more than 55 million people suffer from it (WHO data), but the trend is increasing, projections reach 78 million by 2030! It is one of the main causes of disability and self-sufficiency among the elderly, as well as being the seventh cause of death in the world. In Italy, according to estimates by the Istituto Superiore di Sanità (ISS), about 1,100,000 people suffer from dementia (of which 50-60% have Alzheimer’s disease, about 600,000 people).

Unfortunately, we are talking about a disease whose causes have not yet been clarified, and for which a definitive treatment has not been determined. In fact, the most reliable hypotheses over the past 15 years, which identified the main cause of the disease in the accumulation of beta-amyloid protein on neurons, could be the result of communicative manipulation and, in any case, did not lead to the development of effective treatments. The much-touted aducanumab (the drug approved in the US in 2021) is a disappointing example, which, despite eliminating amyloid plaques, doesn’t seem to give real benefits at all in the face of Risks to those who take it.

Here, researchers attempt to formulate alternative etiological hypotheses that explain the disease in another way. One above all: What if Alzheimer’s was not a disease of the brain, but a disease of the immune system within the brain? This hypothesis (summarized in an article published in The Conversation) was developed by a group of scientists from the Krembil Brain Institute in Toronto (Canada), coordinated by Donald Weaver. It begins by considering that beta-amyloid is not a protein that is produced under abnormal (i.e. pathological) conditions, but a molecule naturally found in the brain as part of the immune system. In the event of a trauma or bacterial infection, the beta-amyloid protein acts to “defend” the nerve cells. But at this point, Weaver and colleagues explain, some kind of biological misunderstanding may occur. Because the lipid layer of bacteria is similar to that of nerve cells, beta-amyloid fails to distinguish between the two different membranes, and ultimately targets the wrong target: not the invading bacteria, but the neurons it was supposed to protect. The amyloid plaques thus “smother” the neurons, causing them to lose their function and cause a progressive cognitive decline in the patient, along with other symptoms related to behavior, mood and personality typical of Alzheimer’s disease. According to this hypothesis, the mechanism of “self-sabotage” of beta-amyloid protein resembles a typical autoimmune reaction, very similar to that of many other diseases caused by antibody ligases. However, so far, drugs used against known autoimmune diseases, such as rheumatoid arthritis, have not been shown to be effective against Alzheimer’s disease. However, Weaver and his colleagues hope that by continuing to search in this direction (that is, by searching for regulators of the immune response) an effective solution will one day be found.

In addition to the autoimmune disease theory, another very recent hypothesis (published in “Molecular Psychiatry”) attempts to offer an alternative explanation for Alzheimer’s: it would be a disease in the mitochondria, the power stations of cells (including the brain), which convert oxygen and glucose into energy. According to this study, a newly discovered genetic mutation in mitochondria is associated with a 20-50% increased risk of Alzheimer’s disease. The gene in question regulates the production of a small protein (called SHMOOSE) which, if present, inactivates the mutation itself. Because the ‘offensive’ mutation is present in about a quarter of the population of European ancestry, the finding could represent an important addition to the (so far few) known genetic risk factors for Alzheimer’s disease.