Despite decades of research into Alzheimer’s, there is still no drug in the making – let alone on the market – that can cure Alzheimer’s patients. How is that possible?
In 1901, clinical psychiatrist Alois Alzheimer meets a 50-year-old female patient with a somewhat mysterious condition in the hospital where he works. It all started with paranoia, her husband, Alzheimer, confides. But then things quickly went downhill and she developed increasingly serious sleep and memory problems. She is also increasingly confused and aggressive. Alzheimer’s interest was aroused and when he learned in 1906 that the woman had died and was given the opportunity to examine her brain, he did not hesitate for a moment. He studies the woman’s brain and discovers, among other things, accumulations of proteins. That same year he shared his findings during a conference with fellow psychiatrists. But they show little interest and for a long time there is little mention of the psychiatrist and his ‘Alzheimer’s disease’.
No cure yet
How different is the situation in 2023. Not only does almost everyone have Alzheimer’s disease; most of us know someone who suffers from it. And for a number of decades, a lot of money and time has been invested in Alzheimer’s research. But so far, almost 120 years after the disease was first diagnosed, it has still not resulted in a cure. How is that possible?
Cause
“The biggest problem is that we still don’t know what exactly goes wrong in the case of Alzheimer’s disease,” says Femke Feringa, neuroscientist at the Vrije Universiteit Amsterdam. Scientias.nl. “We do see accumulations of amyloid or tau proteins on scans – an important feature of Alzheimer’s – but we do not know what causes this.” And if you do not know how a disease arises or what causes a disease, it is obviously very difficult to treat it, let alone cure it.
Over Alzheimer
Alzheimer’s disease is the most common form of dementia; according to Alzheimer Nederland, 70 percent of all people with dementia suffer from Alzheimer’s disease. People with Alzheimer’s often become forgetful at first. At a later stage, they may develop more serious memory problems, become confused, become aggressive or suspicious, and have difficulty with everyday tasks that previously came effortlessly to them. These symptoms are often associated with build-ups of proteins that show up on scans of the brains of Alzheimer’s patients. In concrete terms, this concerns amyloid proteins that clump together between nerve cells in the brain and form so-called ‘plaques’ that complicate communication between brain cells. In addition, tangles of tau proteins often form in the brain cells of Alzheimer’s patients, which disrupt the transport of nutrients within the cell. Although researchers clearly see these amyloid accumulations and tau tangles in the brains of Alzheimer’s patients, it is not yet clear what mechanism underlies them and whether these accumulations and tangles are really the cause of Alzheimer’s or should rather be seen as a consequence (i.e. symptom) of other disease processes in the brain.
Brain
The fact that we still do not fully understand what exactly goes wrong when people develop Alzheimer’s is mainly due to the fact that the disease affects the brain. And we cannot investigate them so easily. “You cannot simply remove a piece of the brain and study it – something you can do with tumors or other tissues, for example,” Feringa explains. “And for a long time we could only control the disease post mortem study, in other words by looking at the brains of deceased Alzheimer’s patients – who had made their bodies available to science. But you actually only see the end stage of the disease.” And so not how it all started.
Animal models
In an attempt to gain a better understanding of the cause of Alzheimer’s, researchers sometimes resort to animal models. Laboratory animals are modified in such a way that they develop an Alzheimer’s-like disease. “Mice are usually used for this,” says Feringa. “But these animal models are not ideal either. Because mice don’t get Alzheimer’s on their own.” In order for them to develop a kind of Alzheimer’s, the DNA must be modified, but even then the clinical picture is not 100 percent similar to that of people with Alzheimer’s. And that is how it remains with this research method.
Celmodel
Fortunately, a third method for conducting Alzheimer’s research has been available for a number of years: using cell models. “And that approach has really opened doors,” says Feringa. Stem cells are made from human skin cells, which researchers then grow into brain cells. “And we can then change things in those cells to better understand the underlying biology of Alzheimer’s.”
Long-term studies
This research with cell models relies heavily on other, long-term studies in which people are followed for a long time and regularly undergo blood tests and cognitive examinations, for example. “These types of studies open the door for so-called genome wide associate studies,” says Feringa. “This compares the DNA of hundreds of thousands of people who at some point develop Alzheimer’s with that of hundreds of thousands of people who remain cognitively healthy. This way we can detect systematic changes that occur more often in the DNA of Alzheimer’s patients. Several potential mutations have already been found in this way. You cannot say that people with these mutations will definitely develop Alzheimer’s, but you can conclude that the mutations are associated with an increased risk of Alzheimer’s. And if we know the functions of these mutated genes, we may also be able to identify the mechanisms underlying Alzheimer’s disease.” Cell models can play a key role in this, because they enable researchers to identify the mutations that occur during genome wide associate studies associated with Alzheimer’s, introduce them into brain cells and then see what happens. “This way we can find out whether – and if so, how – the mutations contribute to the development of the disease. For example, by seeing whether accumulations of proteins also arise in the brain cells into which we introduce these mutations.”
Not perfect either
Although these cell models are promising, they have – just like animal models and post mortemresearch – their shortcomings, Feringa emphasizes. “First of all, it is a cell model and therefore not a 3D structure of the entire brain. Another disadvantage is that it is a young model: in a few weeks we convert skin cells into stem cells that grow into brain cells. This clearly makes the model less representative of brain cells affected by Alzheimer’s, because Alzheimer’s is in fact a disease of old age.”
Obstacles
In summary, the search for a cure is seriously hampered by the fact that we still do not know how Alzheimer’s develops. And that can be traced back to the fact that it is difficult for us to study the brain affected by Alzheimer’s. But there is still an obstacle to overcome, says Feringa. “What also makes possible treatment of Alzheimer’s difficult is that there is a barrier between the brain and the rest of the circulatory system: the blood-brain barrier. This protects the brain and prevents pathogens in the blood from reaching the brain.” But that barrier can be quite an obstacle if, for example, you want to get a medicine into the brain. “It is difficult to get them into the brain in high concentrations, so there is a chance that potentially successful therapies will ultimately fail to reach their destination.”
Hopeful
When you hear all that, you might lose heart. And indeed: there are still many obstacles to overcome and our patience is being put to the test. But Feringa keeps courage. In fact, she says she is “very hopeful”. And that has nothing to do with positive reports that have recently emerged from clinical research (see box).
Lecanemab
In the last two years we have regularly been pleased with positive reports from Alzheimer’s research. Encouraging clinical studies have been conducted and earlier this year the first drug that appears to slow the progression of Alzheimer’s – lecanemab – was approved for use on the American market. But lecanembab and other Alzheimer’s drugs that are still being researched cannot cure Alzheimer’s. “I think all pharmaceutical companies have the ambition to stop the disease,” Feringa notes. “But that turns out to be more difficult than expected. And so they are now focusing on breaking down amyloid plaques.” The idea is that if you remove these, the symptoms will also decrease or at least not worsen further. “Unfortunately, however, it turns out not to be that black and white. Although scans of treated Alzheimer’s patients clearly show that the drugs reduce protein accumulation, we do not see as great progress or reduced deterioration in these Alzheimer’s patients as we would expect. It may mean that these proteins are not the core of the problem.” An alternative hypothesis is that the treatment was simply started too late. “We know about Alzheimer’s that the disease is often underway years before patients develop symptoms. And perhaps the formation of the accumulations in itself already leads to progression of the disease and improvement of the patient’s condition is already a long way from the moment the proteins have accumulated. In that case, we must look for ways to diagnose the disease earlier – before the degeneration of cells starts.”
Even clinical research that seems promising at first glance has pitfalls and does not yet provide the medicine that many patients and their relatives are waiting for. The fact that Feringa remains very hopeful that such a medicine will become available is mainly due to the stem cell models, which she also works with. “They really offer great opportunities for research into these types of diseases,” is Feringa’s belief. In combination with the large data sets that provide more insight into genetic changes that occur more often in Alzheimer’s patients and therefore possibly contribute to the biology and pathology of the disease, she believes that stem cell models have a useful role in the search for the cause of – and therefore ultimately a cure for – for – Alzheimer’s, has already yielded many new clues. “And so there are new routes that we can now investigate further. Of course it remains uncertain. But if you look at the research that is now being done and the insights it provides, I am hopeful that we will find something. Something that – perhaps also in combination with existing or therapies in development – can be used to cure Alzheimer’s.”
2023-12-27 07:30:35
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