How Alzheimer’s disease develops has still not been solved by science. But there is no shortage of theories. For example, there is a growing awareness that infections with viruses and bacteria can trigger the disease.
You would think that after decades of intense scientific research into Alzheimer’s disease, there would be a conclusive explanation for the development of the condition, but there isn’t. We know that clumping of amyloid proteins between brain cells can be a cause, just like tangles of tau proteins in the brain cells themselves. But that is not sufficient as an explanation. There are people in whom large amounts of both proteins have been found in the brain after their death, but who have never developed symptoms of the disease. Conversely, not all victims of dementia have high concentrations of both proteins.
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You would think that after decades of intense scientific research into Alzheimer’s disease, there would be a conclusive explanation for the development of the condition, but there isn’t. We know that clumping of amyloid proteins between brain cells can be a cause, just like tangles of tau proteins in the brain cells themselves. But that is not sufficient as an explanation. There are people in whom large amounts of both proteins have been found in the brain after their death, but who have never developed symptoms of the disease. Conversely, not all victims of dementia have high concentrations of both proteins. Moreover, therapies aimed at combating protein accumulation appear to yield few concrete results. For example, the drug Aducanumab from the company Biogen can counteract the accumulation of the amyloid protein, but it has not been proven to reduce the symptoms of the disease. Still, in early June, the U.S. Food and Drug Administration approved its use in the fight against Alzheimer’s disease — much to the dismay of many. ‘It is typical for our sector’, sighs the world-renowned Alzheimer’s expert Bart De Strooper, active in Leuven (VIB/KU Leuven) and London (University College). ‘There have always been camps that fought each other, such as whether amyloid or tau is the main cause of the disease. Defenders of the amyloid theory now take heart from the fact that the approved drug has an effect on accumulations, while opponents see it as evidence that the protein has only marginal importance, because it does not alter the course of the disease . That confirms the lack of conclusive insights into the pathogenesis of the disease.’ De Strooper also points out the confusion about Alzheimer’s disease and other forms of dementia: ‘Alzheimer is the leading cause of dementia worldwide, but there are forms of dementia that have nothing to do with Alzheimer’s, such as vascular dementia. Dementia also occurs with increasing age. People are indeed aging healthier, implying that environmental factors are important in triggering dementia. Especially in older people we now often see an amalgam of indications, both for Alzheimer’s and other forms of dementia. There seem to be mixed forms.’ There is also a growing understanding that there are different forms of Alzheimer’s that may have different causes. ‘There are not many known direct causes of Alzheimer’s disease,’ admits De Strooper. ‘We only have a good idea of what happens in the rare genetically determined familial forms of the disease, which are clearly triggered by a problem with the production of the amyloid protein. But in the other cases of the disease – which make up 99 percent of the total package and are mostly linked to older age – there is only a small group that seem to have the same cause. We don’t even know if it’s 1, 10 or 15 percent of the cases. If there’s one thing I’m ashamed of after all these years of hard work, it’s that we still don’t know much about the mechanisms behind Alzheimer’s and other forms of dementia.’ This uncertainty makes the sector sensitive to hypes about the results of epidemiological studies, which may or may not be well-substantiated. ‘Can an infection trigger Alzheimer’s disease?’ At the end of last year, the scientific journal Nature headlined an article that examined whether viruses and bacteria could be the cause of the disease. Three herpes viruses and three bacteria have already been linked to the disease. But whether they could be the direct cause of it is unclear. It cannot be ruled out that the chronic infection that triggers an infection can in itself put extra pressure on aging brains. One of the bacteria mentioned is Borrelia burgdorferi: the cause of Lyme disease. ‘Lyme is very fashionable in the medical world these days, so it is also showing up in our sector,’ says De Strooper, somewhat scornfully. ‘But at the moment I see no more than a small connection, whether or not coincidental. The fact that a slightly increased risk of Alzheimer’s may emerge from a large-scale epidemiological study does not mean that one is also the cause of the other. For example, it has been shown that people taking antiviral therapy are 11 percent less likely to develop dementia. But there are many reasons why the connection could exist. For example, people who take antiviral therapies mainly come from higher social classes, who take better care than people from lower classes. Their higher education alone makes them better protected against dementia. Those kinds of possibilities make it extra difficult to put your finger on the wound.’ Another bacteria that has been much talked about is Porphyromonas gingivalis, which plays an important role in tooth decay. Bad teeth have long been associated with Alzheimer’s. A few years ago, a study showed that 99 percent of the examined brains of people who died of Alzheimer’s disease contained a protein produced only by that bacterium. There was even a direct link between the amount of protein and the severity of the disease. But the science isn’t out yet. The wealthy American entrepreneur Leslie Norins offered a prize of 1 million dollars in 2017 to anyone who would prove that an infection can cause Alzheimer’s. In February 2021, he announced that none of the forty candidates who had applied were eligible to collect the prize. De Strooper is also not convinced: ‘There has been a lot of sensationalism about the tooth bacteria as the cause of Alzheimer’s, especially in the press. There are many good reasons to take good care of your teeth, but I still don’t see a direct link to Alzheimer’s disease. For infections it is even more difficult than usual to simulate reality in experiments because there are so many factors at play. But you can’t rule out anything unless you have solid scientific evidence for it. If the link to infections were confirmed, I might have to retrain myself to become an infectiologist. But at the moment it’s too early for that.’ De Strooper certainly does not rule out the possibility that there may be an interaction between infections and, for example, the production of amyloid proteins in the brain: ‘It is the kind of cascade that we see in increasingly complex diseases, such as cancer. It is possible that an overproduction of the amyloid protein, as we see in the genetic forms of Alzheimer’s disease, leads to inflammation in the brain. But it’s equally possible that infection leads to chronic inflammation that in turn promotes amyloid production. We must take this last line of thought seriously, now that there are indications that amyloid could have a protective function against infections. The protein’s precursor is said to have been in the evolution of life for 400 million years in largely unchanged form, implying that it must be useful for something. We ourselves published evidence in Science for the statement that another part of the precursor protein plays an important role in regulating the functioning of the brain. But that doesn’t mean that the amyloid protein can’t cause problems, especially during the aging process or under pressure from genetic factors. A good one can sometimes turn into a bad one in this story too.’ De Strooper is also intrigued by a recent study in Nature, which shows that a gene in the brain that regulates the production of the protein gamma-secretase is stimulated by an infection. Gamma secretase directs amyloid production, so it could be a link between infection and protein production. ‘The question then is always how important such insight into the total picture is’, analyzes De Strooper. ‘Is it something minimal or is it crucial? Another question is whether we can isolate such an insight from the rest of the cascade in order to extract a therapy from it. Unfortunately, I do not know of any old-age diseases that can be treated in a simple way. The form of diabetes that mainly affects young people (type 1) can be controlled with insulin treatment, but that is not possible with the old-age variant of the disease (type 2).’ Genetic factors may also play a role in this context. In some people, the aging process is slower than in others, which can lead to hiccups in the regulation of genes in their brains and make it easier for them to deal with both insidious infections, such as derailed amyloid production. Certainly viral infections can interfere with normal functioning of the DNA of brain cells, many of which have been functioning in older people for eighty years and more, leaving them vulnerable. According to De Strooper, there are also strong indications that the brains of humans and possibly other higher primates (monkeys) are more susceptible to Alzheimer’s than the brains of, for example, mice. The question arises whether the corona crisis will have an effect on what happens in our heads. The coronavirus can infect, or at least affect the brain, resulting in ‘brain fog’ and other concentration problems in people struggling with the consequences of a corona infection. ‘That brings us back to the question of whether there are specific infections that increase the risk of dementia, or whether it is simply an extra load on the brain due to an infection,’ says De Strooper. “It cannot even be ruled out that the high stress level that for many people went hand in hand with the corona pandemic will have an effect on the prevention of Alzheimer’s and other forms of dementia. But unfortunately we won’t be able to determine that until I’m gone. A lot of time is needed for that kind of insight.’
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