“Alzheimer’s disease shows us human existence without any decoration, heartbreakingly bright, fragile, and delicate in all its details,” writes Dutch photographer Alex Ten Napel. The Alzheimer patients shown here are part of a series photographed in an Amsterdam nursing home between 1996 and 2001. For more information, see: www.alextennapel.nl/ copy-of-about-hens-and-roosters-1
The disease has been known for over a hundred years, yet there are still no effective drugs against Alzheimer’s – despite enormous efforts in research and industry. One reason is: time and again, new findings require different approaches. As a result, two major assumptions recently turned out to be wrong. Starting over, then? Not quite.
|Our visit had been scheduled. We ring the bell. My mother opens the door. She beams at us: “Visitors! How lovely! Whom do we have here?” She has absolutely no idea who we are.|
Auguste Deter is only 51 years old at the time of her admission to Frankfurt’s municipal mental asylum in 1901. She is confused, forgetful and unable to cope with everyday life – all symptoms that are more likely to be observed in older people. The neurologist Dr. Aloïs Alzheimer records Auguste Deter’s medical history. After her death, he discovers astonishing changes in her brain: under the microscope, he not only spots numerous dead nerve cells, but also conspicuous protein deposits. These are distinguished into two types: one is of flat coatings between the nerve cells, which are today known as amyloid beta plaques; the other of a structure of fine fibres in the nerve cells known as tau fibrils.
“Alzheimer’s disease shows us human existence without any decoration, heartbreakingly bright, fragile, and delicate in all its details,” writes Dutch photographer Alex Ten Napel. The Alzheimer patients shown here are part of a series photographed in an Amsterdam nursing home between 1996 and 2001. For more information, see: www.alextennapel.nl/copy-of-about-hens-and-roosters-1
Aloïs Alzheimer gives the disease its name. Since the 1960s at the latest, the protein deposits have been regarded as the cause of the destroyed cells and forgetfulness. Typically, however, people fall ill much later than Auguste Deter: for those aged 65 to 70 years, the figure is merely three out of a hundred, while for those over 85, it is one in five.
Alzheimer’s disease is not the only form of dementia, however, although the most common: in Germany, it affects two thirds of the 1.6 million dementia patients. “We speak of Alzheimer’s disease when both deposits, amyloid beta plaques and tau fibrils, occur together,” explains Prof. Dieter Willbold, Director at Jülich’s Structural Biochemistry (ICS-6) division.
|“We’re having soup,” my mother says, radiant with joy. I look inside the pot. A piece of meat floats in the cold water.|
In the search for an antidote to this insidious disease, research has long focused on one of the two deposits: on amyloid beta plaques. One reason was genetic findings. With the help of enzymes, every human being produces amyloid beta proteins from a so-called precursor protein. However, gene mutations of the precursor protein or enzymes may occur. This can result in the formation of a particularly large number of amyloid beta proteins. Those affected fall ill with Alzheimer’s very early in their lives. A small Icelandic population, on the other hand, has developed a mutation through which the body hardly produces any amyloid beta proteins. This apparently makes these people almost resistant to Alzheimer’s.
|She has meanwhile recognised us by our voices and is happy that we are with her.|
On the basis of these findings, an excess of amyloid beta proteins was long regarded as the main cause of plaques and, thus, of the disease. Hence, two ideas were at the centre of attention: if, using imaging methods, the plaques can be visualised early, the disease can be reliably diagnosed. If an active substance can be found that either destroys the amyloid beta proteins responsible for the plaques or prevents them from developing in the first place, the disease is defeated. Unfortunately, both ideas turned out to be wrong. Although some drugs that are currently being developed and tested reduce deposits in the brains of those affected, none of them has been able to stop mental deterioration.
|“How was your trip from Aachen?” she asks. We haven’t lived there for over six years.|
Another indication that counts against the plaques as a cause was provided by the much-noticed Nun Study. Since 1986, the American epidemiologist David Snowdon and his research team have been continuously documenting the mental and physical condition of almost 700 nuns aged between 75 and 107. The nuns decided that after their deaths, the brains of the deceased are to be donated to science. It turned out that numerous participants of the study showed the typical deposits in the brain and were mentally fit up to old age all the same.
After these setbacks, several large corporations have thrown in the towel, either completely withdrawing from Alzheimer’s research or discontinuing studies, as did the Eli Lilly Group in 2016 – after more than 27 years of research and development and an investment of around USD 3 billion – and the companies Pfizer and Merck at the beginning of 2018. Yet research does not have to start from scratch. The previous findings continue to form the basis. However, potential active substances might have to set in one step earlier.
Insoluble amyloid beta deposits between nerve cells
Tau protein entanglements in nerve cells
Small soluble aggregates of a few amyloid beta molecules
|“She asks me dozens of times a day what day of the week it is.” My father is visibly struggling to retain his composure.|
Physicians and scientists by now assume that a precursor of amyloid beta plaques is the true culprit. “It is obvious the so-called amyloid beta oligomers impair brain function by disrupting the processes at the synapses, the contact points between the nerve cells,” explains Dieter Willbold. The oligomers are formed when the molecules of the amyloid beta protein randomly combine to form small molecule groups. The flat plaques that Aloïs Alzheimer discovered only develop when these molecular groups are grouped further. These are insoluble and accumulate between the nerve cells. The oligomers are different: they are smaller than plaques, soluble and can therefore move freely in the fluid of the brain. “However, it was only modern technology that made it possible to discover the oligomers about 15 years ago. They are now regarded as an important driver of Alzheimer’s disease,” says the Jülich expert.
It appears that they also have an influence on the other deposits that Alzheimer had discovered: the tau fibrils. Their formation can be triggered by amyloid beta oligomers, among other things. The oligomers dock to the surface of nerve cells, triggering a momentous signal inside the cell. It activates an intracellular enzyme that alters another protein: tau proteins. Normally, these help to stabilise the structure of nerve cells and their transport pathways. But the alterations make these proteins “sticky”. They accumulate and form insoluble fibres, the fibrils. The result: the affected cell dies.
And things get even worse. Fatally, nerve cells exchange tau proteins with each other. They do not differentiate between normally structured tau and the altered, sticky variant. The result is a snowball effect in which more and more altered tau proteins are passed on and more and more of them become entangled. The irreversible mass death of nerve cells begins. At this stage, the first mental impairments become apparent in those affected.
|“Yesterday she took her entire medication for two days at once,” my father says.|
Combinations of active substances targeting both amyloid beta oligomers and the altered tau proteins are therefore considered promising. Dieter Willbold and his team have initially tackled one of the two possible targets. They developed a protein molecule – a peptide called PRI-002 – that destroys the amyloid beta oligomers.
The active substance had the effect that the spatial orientation of mice with symptoms similar to Alzheimer’s disease improved again. They were able to remember the position of a rescue platform in a pool. Without the active substance, they kept swimming around erratically in all experiments without finding the rescue platform hidden below the surface – in contrast to healthy mice, which always headed purposefully towards the platform after the first experiment.
In September 2017, Priavoid GmbH was spun off from Forschungszentrum Jülich in order to develop a marketable drug from the active substance. Following successful pre-clinical safety and tolerability tests, the Phase I clinical study began in April 2018, in which around 40 healthy test subjects take the active substance to find out how well they tolerate it. “The tests with the first subjects have so far not revealed any side effects,” reports Willbold.
However, patience is needed before any possible approval of the drug: on average, seven years elapse between the start of a Phase I trial and marketing approval, with only one-fifth of all active ingredients tested making it from Phase I to market entry. And it takes money, a lot of money: development costs can run into billions.
Not only suitable active substances are needed, however, but also better studies to test their effectiveness, as the researchers agree that one important reason for the failure of numerous previous studies is the selection of test persons. So far, patients with mild to severe signs of dementia have been recruited for such studies. “However, since the disease spreads decades before the first mental impairments in the brain, it is crucial to include those in the studies who are affected and do not yet show symptoms,” says Dieter Willbold.
The basis for this is a reliable and, above all, early diagnosis of Alzheimer’s disease. Researchers around the world are working hard to achieve this. Only for a few years has it been possible to visualise amyloid beta plaques and tau fibrils in patients using imaging methods. And thanks to advanced technology, it is now also possible to detect specific biomarkers in the spinal fluid that reveal, even up to 15 years before the first signs of dementia, whether someone is highly likely to develop the disease.
|My mother hands me the third piece of cake: “Child, you haven’t had any cake yet, you have to try this one!”|
“It would be ideal to have a low-priced blood test that shows even the slightest changes in brain metabolism before the majority of the nerve cells are irretrievably lost,” says Dr. Oliver Bannach, biophysicist and member of Dieter Willbold’s team. The Jülich scientists have also targeted the amyloid beta oligomers for such a diagnostic procedure. Oliver Bannach describes the status of the procedure: “We detect even the smallest amounts of oligomers in the spinal fluid of Alzheimer’s patients using fluorescent probes.” The researchers found a direct correlation between the increasing amount of amyloid oligomers and the progression of the disease.
“Still, our goal is a blood test,” says Bannach, who, to commercialise the test, founded attyloid GmbH in February 2018 together with colleagues from Forschungszentrum Jülich and Heinrich Heine University Düsseldorf. “Only specialists should take fluid from the spinal cord, blood can also be taken by the family doctor. This would allow patients to be diagnosed much faster,” he emphasises.
|“No, we didn’t take her to hospital. What’s the point,” my father asks.|
He is therefore currently expanding the portfolio with his employees. The company is working on the detection of different tau aggregates and other molecules in blood samples in order to be able to distinguish between different neurodegenerative diseases earlier and, above all, better.
Despite all the progress made, however, the question remains as to why some people remain fully alert despite overwhelming biological evidence suggesting Alzheimer’s dementia. The Nun Study mentioned above – more precisely the personal biographies of the participants – provides a hint for solving the riddle. Despite numerous amyloid plaques and tau fibrils in the brain, nuns who had a rich vocabulary in their youth did not suffer from Alzheimer’s disease at all or fell ill much later than women with only a simple form of expression.
“We were able to confirm this effect in our studies,” says Dr. Gérard Nisal Bischof from the Jülich Institute of Neuroscience and Medicine (INM-3). The researchers found, in the same disease stages, a significantly higher number of amyloid plaques and tau fibrils in the brains of patients with a higher level of education than in patients with a lower level of education.
|My mother hasn’t left home in several years. “She’s afraid of getting lost,” says the lady from the nursing service.|
The level of education, but also the healthier lifestyle that is usually associated with it seem to be directly linked to the extent to which the brain can compensate for deficits caused by the progressive cell death. Apparently, the brain tries to shift tasks from areas that are already dead to others.
Bischof also stresses the correlation between physical and mental fitness. Researchers found that people with uncontrolled high blood pressure have more amyloid beta deposits in the brain than those with low blood pressure. This finding could be proven even for the inherited form of Alzheimer’s. “So, sport is extremely important, even if it’s just a walk. Because what is good for the heart is good for the head,” he emphasises.
“Dealing with scientific facts as a journalist is easy. Experiencing and documenting the mental decline of one’s own mother is hard work,” says our author Brigitte Stahl-Busse. Her 84-year-old mother has been suffering from rapidly progressing dementia for seven years.
|We want to leave. I can’t find the car key. Is this how it begins?|
Images: Alex ten Napel