Around 50 million people worldwide suffer from dementia, and in almost 70% of the cases the disease has the same name: Alzheimer’s. According to the World Health Organization, 10 million cases are diagnosed each year, and projections speak of 82 million people being affected by 2030 and 152 million by mid-century. Modern medicine and improved living standards have increased life expectancy, but Alzheimer’s and other neurodegenerative diseases threaten to truncate the prospect of a long and full old age. Unfortunately, Alzheimer’s is still an idiopathic disease, meaning that its cause is unknown. Recently, a new pathway has been opened that adds to the traditional hypotheses about its origin: what if it were really an infectious disease?
Since 1906, when German psychiatrist Alois Alzheimer described the disease that bears his name, two anomalies have been identified in the brains of people affected: amyloid plaques and neurofibrillary tangles. Later studies discovered that both are protein deposits with a defective folding, beta-amyloid in the former case and tau in the latter. These observations gave rise to the two main hypotheses about the cause of the disease, which attribute it respectively to one of the two types of deposits. As explained to OpenMind by Lary Walker, a neurologist at Emory University (USA), Alzheimer’s disease “most probably affects older people because aging cells lose their ability to dispose of aberrant proteins such as misfolded amyloid-beta and tau.”
If these proteins are primarily responsible for the disease, and not an effect subordinated to other causes, it can be assumed that the defective folding would first arise as a result of a genetic mutation that would alter the protein produced by a particular cell. “In virtually all cases it originates within the brain of the affected persons,” says Walker. But how can this defective shaping of the protein spread and colonise large regions of the brain?
A protein that transmits its defect
In 2006, a team of researchers headed by Walker and Mathias Jucker, from the University of Tübingen (Germany), demonstrated that the defective beta-amyloid is capable of seeding the appearance of plaques by spreading its defect to other healthy copies. In other words, the Alzheimer’s protein would behave like a prion, the agent responsible for mad cow disease. This pathology became famous in the late 1990s when researchers began to detect cases of transmission to humans through the ingestion of products from sick cows. The cause is an abnormal prion protein that transmits its defect to other normal proteins. As a result, the affected proteins become sticky, clumping together to form deposits that cause the death of neurons. “We found that this molecular mechanism is virtually identical for amyloid-beta and the prion protein,” Walker summarises.
Walker and Jucker’s finding ushered in a new approach for research into Alzheimer’s and other neurodegenerative ailments, which came to be seen as unconventional infectious diseases. But as with the human variant of mad cow disease, a contagion is something that would only occur in very rare cases. According to Walker, “there is still no evidence for the transmission of Alzheimer’s disease under everyday circumstances.” Spontaneous mutation would continue to be the main origin of the disease.
However, these exceptional situations do exist. In recent years, several studies have shown that contamination with beta-amyloid in surgical instruments or in growth hormone preparations from human cadavers —a source that is no longer used for treatments— can seed the growth of typical Alzheimer’s plaques in the brain. Even so, Walker says it is not yet known “whether fully-manifested Alzheimer’s will eventually emerge in at-risk subjects.”
But the prion hypothesis does not settle the search for the causes of Alzheimer’s. Although it is a crucial piece of the puzzle, it is necessary to fit it into the framework that other investigations have been piecing together, especially the intervention of certain genetic factors that correlate with the disease; specifically, APOE4, a variant of a protein (apolipoprotein E) involved in the metabolism of fats.
The bacteria of gum disease
According to David Holtzman, neurologist at the Washington University School of Medicine in St. Louis (USA), “APOE4 enhances the ability of amyloid-beta to convert from a soluble to an insoluble form.” Thus, this protein would facilitate the seeding of amyloid plaques, which would explain its relationship with the disease. And this mechanism adds yet another piece to the puzzle, since APOE4 is not the only factor that can act in this way: “Work in animal models has shown that certain infectious agents can facilitate amyloid seeding,” adds Holtzman. And while this effect has not yet been demonstrated in humans, it points to the possibility that some conventional infections may encourage the development of the disease.
So far, several infectious agents have been proposed as possible candidates. The bacteria Porphyromonas gingivalis, the cause of pyorrhea or periodontitis (gum disease), has recently gained special interest. At the beginning of 2019, the work of a large international team of researchers not only revealed that the bacteria is present in the brains of Alzheimer’s patients, but also that oral infection in animals leads to the invasion of the brain by this microbe and the production of beta-amyloid. Furthermore, researchers have found toxic enzymes produced by the bacteria, called gingipains, that appear before the development of the disease.
An additional aspect that reinforces the possible role of P. gingivalis in Alzheimer’s is that the authors have linked the bacteria to other pieces of the puzzle. “We will soon publish data showing that the APOE proteins are a target of gingipain cleavage, with APOE4 being more susceptible. This gingipain cleavage causes loss of the normal APOE functions, like inhibiting excess inflammation in the brain,” co-director of the study Stephen Dominy, co-founder of the company Cortexyme, told OpenMind. What’s more, gingipains also exert a detrimental effect on the tau protein.
A possible solution
Nevertheless, other experts are cautious about this new hypothesis. Holtzman states that “more work needs to be done,” while for Walker “there is evidence that at least some infectious agents increase the likelihood of developing Alzheimer’s, and as such they can be added to a long list of risk factors for the disease.”
In any case, it will not take us long to know if the P. gingivalis route can be helpful in attacking a disease that is currently incurable: along with the problem, researchers have proposed the solution. Dominy and his collaborators have developed an orally-administered gingipain inhibitor called COR388, which in animals reduces the presence of the bacteria in the brain, blocks the production of beta-amyloid and prevents neuronal death. A phase 1 clinical trial has already been completed in humans that has demonstrated the drug’s safety. “We have now initiated a large Phase 2/3 clinical trial in the US and Europe,” says the researcher.
“If COR388 is effective in the treatment of Alzheimer’s, then a vaccine might be considered that would be given when people are very young, prior to infection with P. gingivalis,” concludes Dominy.