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Pictures of the Future
The Magazine for Research and Innovation
 

Demographic Change (REPRINT)

Alzheimer‘s Disease: Village of Forgetfulness

Yarumal, a small Colombian village, has an unusually high percentage of people with Early Onset Alzheimer’s Disease.

A large number of unusually young people in the mountainous region of Antioquía in Colombia suffer from a hereditary form of Alzheimer’s disease. An international team of researchers is testing a special medication to be administered long before any symptoms appear. If this approach proves effective, it would be a major breakthrough in the treatment of Alzheimer’s. A pilot study in Medellín is drawing on imaging technology from Siemens.

Dr. Andrés Villegas takes off his digital watch and his wedding ring and carefully attaches the ring to the same clip that also holds his ID card. He slowly rolls up his shirtsleeves and puts on a blue smock that covers everything except his shirt collar and gray tie. Villegas now puts on a pair of latex gloves and – just to be on the safe side – a second pair over them. Only after he has done all this does he remove the cover from a white plastic tub in front of him and immerse his hand in a yellowish liquid. The tub contains half of a brain – and brains are Villegas’ specialty. Villegas is the Director of the biobank at Universidad de Antioquía in the northwestern Colombian city of Medellín. It has a collection of about 200 human brains. Villegas has personally dissected and prepared around three quarters of them for further study.

He now carefully places the dripping half brain onto a stainless steel tray. “This brain has shrunk considerably,” he says “Look here and you can see some conspicuously deep grooves that look like the wrinkles in a dried-out grape.” He pauses and then gives the diagnosis. “This patient was only 56,” he says, “and what you see here is the result of early-onset Alzheimer’s disease.” Nowhere else in the world are as many people afflicted by this special form of dementia as here in Colombia, in the department of Antioquía.

The Paisa Mutation

Although early-onset Alzheimer’s is very similar to the typical form of the disease, there is one major difference – namely, that in some cases the first symptoms occur before the victim turns 40. It begins with forgetfulness and progresses to disorientation and delusional ideas. Individuals afflicted with this form of Alzheimer’s reach the final stage of the disease at the age of 47 on average. By contrast, the more common form of Alzheimer’s sets in at the age of 65 or older. Early-onset Alzheimer’s is caused by a simple genetic defect on Chromosome 14. Over a period of around 300 years, this defective gene has spread throughout a widely branched family that now has around 5,000 members. Experts refer to it as the “Paisa mutation” because the people living in the region around Medellín are known in Colombia as Paisas.

Villegas gets to know many of the patients while they’re still alive. After they die, he removes their brains and studies them. “A brain can tell you a lot, but it can’t tell you everything,” he says as he places the half brain back into the formalin solution. “The ideal research case is when you can follow the course of the disease while the patient is still alive.” The other half of the brain he’s studying is stored along with hundreds of others in a large freezer. Villegas does the same thing with all the brains: He puts one half in a solution and the other in ice at -78 degrees Celsius.

Dr. Adam Fleisher from the Banner Alzheimer’s Institute in Arizona has traveled from Phoenix to Medellín specifically to contribute to the launch of an ambitious prevention trial, which is part of a program known as the Alzheimer’s Prevention Initiative. “We want to develop a preclinical treatment for Alzheimer’s,” Fleisher explains. “In other words, we’re aiming to come up with a treatment that can prevent the disease or delay its outbreak, or at least slow its progress.”

Most drugs for treating Alzheimer’s that have been tested to date have proved to be more or less insufficiently effective for fighting this terrible disease. Fleisher and his research colleagues believe this may be due to the fact that the medications were administered after it was too late for the patients. “You may have to start the treatments before the onset of symptoms,” Fleisher explains. “We’ve been able to show that Alzheimer’s causes changes to the brain long before patients display the first signs of dementia – in some cases, 20 years before the first symptoms occur. For example, researchers have discovered that the onset of Alzheimer’s is preceded by the accumulation of plaques of beta amyloid proteins. These plaques form a type of crust in brain cells, which then slowly die as a result. By the time patients become forgetful, their brains may already be irreparably damaged.” Indeed, in many cases the patients’ brains have already significantly shrunk by the time they and those around them notice the first signs of forgetfulness.

“We think it’s likely that we have the right weapon for fighting Alzheimer’s already – the problem may be that we are not using it until it’s too late,” says Fleisher. The weapon being tested in the study in Medellín is called crenezumab. This medication is designed to attach itself to the amyloid and allow the patient’s immune system to render the protein harmless before it begins forming plaques.

Perfect Population

How can the researchers know whether their hypothesis is correct? Should they give crenezumab to healthy people, for example? If they did, they would have to wait decades to find out whether the test subjects displayed fewer cases of Alzheimer’s than a control group that would not have been given any medication. Such a plan would therefore be impractical at best. A population predisposed to developing Alzheimer’s, on the other hand, would be ideal – which is where the Antioquía patients come in. That’s because all it takes is a genetic test to reliably determine if these individuals will eventually be afflicted with the disease. Such patients therefore constitute a perfect population for clinical studies of the medication.

Although patients with early-onset Alzheimer’s are also to be found in other parts of the world, the large number of cases in the region around Medellín helps to ensure a high level of reliability for the results of the clinical study. That’s why the study in Antioquía will soon be under way with 300 participants, all of whom are between the ages of 30 and 60 and have not yet shown any symptoms.

Excellent imaging technology is an essential part of the research program. The Banner Alzheimer’s Institute has made use of Siemens’ latest generation of PET-CT devices (a combination of a computer tomography and a positron-emission tomograph) to make amyloid plaques and their continuing growth in Alzheimer’s patients visible in detail for the first time. Fleisher and his colleagues are now hoping that such plaques will never form to begin within the patients in Antioquía who will be treated with crenezumab at an early stage. “We divided the participants into two groups,” says Fleisher. “One group will be given the drug, the other group will receive a placebo. Repeated MRI, PET-CT scans, spinal fluid assessments and cognitive testing in Medellín will help us to draw conclusions over the next two to five years regarding the effectiveness of the medication.”

The tragedies caused by the frequency of Alzheimer’s in the region can be seen in towns such as Belmira, Angostura, and Yarumal, all of which are about a two hours’ drive north from Medellín. Most of the people afflicted with early-onset Alzheimer’s live here, and this degenerative brain disease has cut down many in the best years of their lives. There are no adequate facilities to care for them in these areas. They are usually taken care of by family members. Maria is one of these caregiver.

Family Affair

Maria is 83 years old. Despite the fact that she doesn’t carry the Paisa mutation, her life has been shaped by Alzheimer’s. Her husband died of the disease over 20 years ago, and four of her 16 children suffer from it. Her son Alejandro died three years ago from Alzheimer’s at the age of 56. It was so difficult to care for him that he was sometimes tied to a chair to keep him from wandering around aimlessly. “This is not an isolated case,” says Claudia Madrigal, a psychologist at the hospital in Yarumal. It has barred windows, a few horses are tied at the hospital’s entrance, and a poster in the reception area advertises for Alcoholics Anonymous.

“Thirty years ago, nobody knew what was going on here,” Madrigal says. “People got used to their middle aged relatives becoming forgetful, then aggressive, and finally demented and wasting away. At the time, many people believed a supernatural force was destroying people’s souls, so the sick individuals were locked away and their meals were given to them under the door. Only rarely did families allow an autopsy after the patients died. However, attitudes have changed over the last 20 years.” This change was mainly due to Dr. Francisco Lopera.

Lopera works in the Department of Neurosciences at Universidad de Antioquía. When he was a child, he used to live in Yarumal, where he began noticing the strange frequency of occurrences of dementia during the early 1980s. “It was a puzzle that I wanted to solve,” he explains. Lopera and Lucia Madrigal, Claudia’s aunt and a nurse at the time, went from house to house asking for blood samples from afflicted patients. He also visited wakes and asked family members for permission to examine their loved ones’ brains. Amazingly, he did all this during a time when violent drug gangs controlled the region. Lopera was the first to discover that the sick people of Yarumal were suffering from a special hereditary form of Alzheimer’s.

Bisected Brains

It’s not just Colombians who urgently hope for progress to be made in the treatment of Alzheimer’s. The number of people afflicted with the disease worldwide will increase dramatically over the next few decades, largely as a result of higher life expectancy. That’s because more than 95 percent of Alzheimer’s cases around the world correspond to the typical form of the disease rather than early-onset Alzheimer’s, and the likelihood of a given individual becoming afflicted with Alzheimer’s doubles every five years from the age of 65. “If we could delay the average age when Alzheimer’s sets in by five years, we could reduce the absolute number of cases by 50 percent,” says Lopera. This would be a huge help not only to many Alzheimer’s patients and their families but also to healthcare systems, because proper care can be quite expensive. According to estimates, the total cost of dementia illnesses worldwide in 2010 was more than $600 billion, which corresponds to around one percent of the gross world product.

“People here often begin experiencing a nagging dread when they turn 30.”

The dramatic economic consequences of Alzheimer’s are plain to see in Yarumal as well. For example, many people have to quit their jobs and sometimes children have to leave school in order to care for sick relatives. The fate suffered by Maria’s family is not uncommon, according to Claudia Madrigal: “It’s not unusual to have three or more Alzheimer’s patients living under the same roof. After one dies, the disease soon breaks out in another family member. I’m currently helping a family with 14 children, seven of whom suffer from Alzheimer’s.

The emotional stress on the relatives is enormous in such cases.”Madrigal mainly treats anxiety and depression; suicide rates and drug consumption in the region are high, she says. “People here often begin experiencing a nagging dread when they turn 30,” she explains. “If they forget small things, they immediately interpret it as a sign of the sickness. Even teenagers ask themselves who will take care of them later, or whether they will want to have children.”

The Alzheimer’s study has now become the only shimmer of hope for many of the afflicted individuals, even though nobody knows for sure whether they themselves will benefit from its results. In order to ensure reliable results, study participants aren’t even told whether they carry the mutation. Nevertheless, hundreds have volunteered to take part. “The participants simply want to help the millions of people who might benefit from more effective Alzheimer’s treatment in the future,” Madrigal says.

When asked if she herself worries about getting the disease, she replies, “My ancestors were barely affected, so it’s very likely that I’ll remain healthy.” Then she suggests talking to the local priest to get more information. That’s because Lopera discovered one key to the disease plaguing the community in the nearby rectory – in the church records, which contain all the information and dates concerning births, marriages, and deaths. Everything has been preserved in these records, which go back for centuries. Lopera used the documents to create family trees that put him on the right track, tracing the genealogies of affected families back to the year 1700, and putting together the pieces of a puzzle that eventually told him what he needed to know.

The route from the hospital to the church leads through the steep and narrow alleys of Yarumal. Loud music can already be heard coming from bars here during the afternoon; teenagers stand on street corners. A young mother is holding her baby in her arms. The child is carefully wrapped in a beige blanket to keep warm in the cool mountain air. The arrival of the infant is accompanied by a question that is extremely hard to contemplate – will the memory and then the mind of the infant start to disintegrate in 40 years or so? Fear and hope are never far apart in Yarumal.

Father Oscar Umberto Posada Ruíz knows a lot about this. Ruíz is one of the priests who serve the community and offer comfort to Alzheimer’s victims and their relatives. “Many people first believed the sickness was a form of witchcraft, but of course I convinced them that this was not the case,” Ruíz explains. “They asked me questions like ‘Why me? I’m a religious person!’ I would tell them it was simply a disease that they weren’t responsible for – it wasn’t a punishment from God. Evil simply exists in the world. Some people lose faith and trust in the church, but others grow more attached.”

Madelyn Gutierrez knows figures like that by heart. She sits in a windowless office in Medellín located not too far from the Biobank and its halved brains. The air conditioner rattles lightly as patients assemble for the study that will begin shortly. Gutierrez is the young psychologist who is coordinating the study and ensuring that it adheres to clinical trial standards. Among other things, the 300 participants will undergo tests to determine their cognitive capabilities and will also be sent on a regular basis over the next few years to the nearby Pablo Tobón Uribe Hospital for brain scans carried out with PET-CT devices from Siemens.

Gutierrez will also make sure the patients come to Medellín from their villages and show up on time for the examinations. “We need to comply with the highest standards for clinical studies, including ethical standards,” she explains. “I’m the one in charge of reminding everybody to be meticulous with their documentation, because everything we do must be transparent.” Even minor methodological errors could jeopardize the results of this sophisticated and costly study.

“The big question is whether the beta amyloid in the brains of Alzheimer’s patients actually causes the disease, or if it’s merely an additional symptom,” Gutierrez says. “If it’s the cause, then drugs that inhibit its accumulation should help to prevent the disease, but if the plaques are a secondary sign, you would expect that the drugs would be ineffective even if they are administered at a very early stage. So far this has been a matter of discussion, but through this study we want to settle the issue once and for all.”

Some scientists doubt that amyloid holds the key to understanding Alzheimer’s, wondering whether the key may rather be a protein called tau that makes up neurofibrillary tangles. Changes in other biomarkers, such as the tau proteins, have in fact been observed in Alzheimer’s patients but they need not contradict the amyloid hypothesis.

“One of the goals of our trial is to provide a better test of the amyloid hypothesis than the trials that have been conducted in clinically affected patients, when the treatment might be too little too late,” says Dr. Eric Reiman, Executive Director of the Banner Alzheimer’s Institute.Institute researchers did in fact conduct an initial small-scale study that involved flying a few dozen patients from Colombia to the institute in Phoenix, in the United States, where among other things they were examined with Siemens PET-CTs for signs of amyloid plaques. The patients had to come to Arizona because the complex examinations couldn’t be carried out in Medellín at that time.

International Attention

Today, no one has to be flown to the U.S. for the more extensive current study, because the complex imaging technology is now available at Pablo Tobón Uribe Hospital in Medellín. The hospital is considered one of the best in Colombia and is well prepared for the study’s numerous participants. Dr. Héctor Zuluaga offers a look at the Siemens magnetic resonance tomography unit, which can reveal brain shrinkage in dementia patients, as well as the recently procured Siemens PET-CT, which makes amyloid plaques visible. The radioactive isotopes needed to operate the units are still being flown in from Colombia’s capital, Bogotá, but a Siemens cyclotron will soon go into operation in Medellín to supply the hospital with isotopes. “We often ask our patients to rate the hospital’s technical equipment, and we have an average grade of 4.99 – from a maximum score of five,” Zuluaga explains.

Just a short drive from the hospital, past the Christmas lights for which Medellín is famous throughout Colombia, training has already begun for the study’s clinical staff – several dozen medical professionals who will work directly with participants. Reiman and Dr. Pierre Tariot, both Directors of the Banner Alzheimer’s Institute, have already arrived in Medellín, where they are now quizzing their physician colleagues from Colombia in a small lecture hall. “Our goal is to detect problems early on,” Tariot says.

“So what would you do if a patient developed symptoms during the study?” A young female doctor raises her hand: “I would talk to the patient and his or her family, and remind them that the patient is participating voluntarily and that all data will be dealt with confidentially.” Tariot is satisfied with this answer, and Lopera, who’s sitting in the first row, also nods. This is all a dream come true for Lopera – and right before Christmas.

Infectious Prions?

For decades, Lopera has been laboriously processing data, some of which he collected in life-threatening situations in the mountains of Colombia, and he has done all this largely unnoticed by the international research community. His first research project related to early onset Alzheimer’s had a budget of $500. Then, a few years ago, the floodgates opened as Alzheimer’s researchers from around the globe suddenly became interested in Lopera’s patients. The clinical study that is now beginning has a budget of more than $100 million.

Lopera’s hair has by now turned white, but he’s full of energy and optimism. “We believe in the amyloid hypothesis,” he says, “and if it turns out to be correct, the study would be a huge success, because it could bring us closer to an effective treatment for Alzheimer’s.”

And if the hypothesis cannot be confirmed? “The study would still be a success,” Lopera explains, “because we would at least then know that we have to start all over again in Alzheimer’s research.” In the best case, there might be a drug in a few years that could for the first time slow down the progress of Alzheimer’s. “When I was a kid, I was very interested in UFOs and I wanted to be an astronomer or an astronaut,” Lopera recalls. “Then somebody told me UFOs only exist in one’s brain. So I became a doctor – a doctor who looks into people’s brains.”

Villegas is now cleaning up his lab. Hygiene is extremely important – the tissue samples might, for example, be contaminated with highly infectious prions. Villegas closes the top of the tub containing the half brain disfigured by Alzheimer’s. “Some people look at a brain and see only a wrinkled mass,” Villegas says. “I look through the microscope and see complex structures and entire landscapes.” After a brief pause, he adds, “Brains are marvelously beautiful.”

 

Disclaimer: The products/features (here mentioned) may not be commercially available in all countries. Due to regulatory reasons their future availability cannot be guaranteed. Some products may still be under development, in which case their future availability cannot be ensured.

Andreas Kleinschmidt
Picture credits: fromt top: 1. picture T. Heisler/laif