A group of families in Colombia, who carry a rare mutation that causes the disease, has become a focal point for the search for a cure
When Alejandra was a 16-year-old girl, sometime in 2007, she had ambitions like any girl her age. She attended middle school in Medellín, one of the largest cities in Colombia. After school, she spent every free hour with friends at popular hangouts around the city.
Then her mother, Yolanda, began to lose her memory. The quiet but self-aware woman would greet a guest, and a few minutes later repeat the greeting, and then again. In her mid-40s, Yolanda had already developed early-onset Alzheimer's disease. For Alejandra, this meant that her youth had come to an end. Whether she wanted to or not, she was forced to take on most of the responsibility for the care of her mother, whose helplessness increased over time.
Alejandra, now 24, has since moved to the nearby city of Copacabana, where she shares an apartment on one of the high floors of a housing estate with her aunt, two uncles, her nine-year-old daughter Luna, and her 17-year-old sister Carolina, who dropped out of high school to help out. Her mother can no longer talk or walk and spends most of her time leaning forward in a chair. One of the uncles, 51 years old, also suffers from dementia.
Every day the girls cook for the two Alzheimer's patients. They feed the mother and Uncle Albeiro through feeding tubes. They bathe them and carry them to bed. They repeat this routine day after day, without breaks for birthdays or vacations. "I had hopes," says Alejandra. "I had plans. I wanted to learn. I wanted to be a nurse. So many plans I haven't been able to carry out... I already feel old."
Alejandra had an ominous feeling about her fate long before her mother was officially diagnosed. As a child, she remembers how her mother took care of her grandmother, who also had Alzheimer's. Many people in this corner of the world share Alejandra's experiences. She and her family are among more than 5,000 people in 26 extended families across the Colombian province of Antioquia who are at high risk of developing a rare genetic variant of Alzheimer's. Paisa, the name of the mutation that causes the disease, is the regional nickname for the people of Antioch. The mutation, found on chromosome 14, appeared during the time of the conquistadors, in the 16th century. When a copy of the defective gene is inherited from the mother or the father, the children will definitely get the disease at a young age.
Only 35 percent of the more than 20 million Alzheimer's cases worldwide have familial Alzheimer's, as this form of the disease is known. (The disease has received extensive public relations recently due to Julianne Moore's Oscar-winning role in the film Still Alice, as a woman with Alzheimer's at a young age.) However, in the extended families near Medellin, familial Alzheimer's is alarmingly common. A paisa mutation is found in more than 5,000% of the 26 people belonging to the 50 families. Most carriers are diagnosed with the disease before the age of XNUMX.
The high probability of Alzheimer's in the people of Antioch recently began to attract the attention of experts around the world. Attempts to develop a cure for Alzheimer's have failed for years. The frustration caused to scientists as they watched drug after drug fail led them to conclude that once symptoms are present, it may be too late to stop the progression of the disease. That is why they began to focus on prevention. Instead of treating people who are already showing signs of dementia, it may be necessary to give experimental drugs to people who are still healthy, and then see if they stay healthy or develop Alzheimer's.
Conducting such trials in the general population would be long and expensive due to the difficulty of predicting when, or if at all, the disease would develop. This difficulty does not occur in Colombian families. The families carrying the fateful mutation were recruited into a clinical trial to test a drug and see if it could prevent Alzheimer's. Because they have lived with the grim reality of the disease for centuries, they are a vital link in the search for preventative treatments.
The vision
The shift to focus on prevention in the fight against Alzheimer's rests on the most important advances in research on the disease in recent years. The current clinical study uses magnetic resonance imaging (MRI) and positron emission tomography (PET), brain scans combined with a lumbar puncture to detect the telltale signs of Alzheimer's. With the help of these methods, researchers can follow changes that occur in the brain of a person who is expected to develop dementia, sometimes decades before the official diagnosis of the disease is made.
These new tools can help determine what will happen if a drug, perhaps even one that has already failed in previous clinical trials, is tried on patients years before they suffer from forgetfulness. If the brain changes characteristic of Alzheimer's do not show up in the scans, and the patients do not see cognitive changes, it would be possible to assume that the drug helps prevent the disease. Due to the ability to predict the outbreak of the disease during menopause in Antiochians carrying the Faisa mutation, there is great interest in recruiting them into clinical studies to test prevention methods.
A key figure in this journey is Francisco Lopera, a 63-year-old neurologist who began researching the Antioquia families long before anyone thought they would be important to Alzheimer's research. Lufra spent his youth in Yrumal, a town where many of the families carrying the Paisa mutation live. He remembers neighbors from his childhood who went insane during menopause. After completing his postdoctoral studies in Belgium in the late 80s, he believed he could make more progress in Alzheimer's research as a researcher at Columbia than if he pursued a career at a European research institute. At that time, he had already located the first family that suffered, as he suspected, from a genetic version of the disease. In 1987 he returned to Colombia, where he accepted a position as a neurologist at Antioquia University and returned to his research on families affected by Alzheimer's at a young age.
Lopera, today the head of the neurobiology group at the university, drew extensive genealogies of the 26 families who contracted the disease over the decades. His research involved difficulties not found in Europe. For example, in order to maintain regular contact with the various families, a military convoy was sometimes needed to cross battle zones between the Colombian army and guerrilla groups. There were times, about 15 years ago, when the danger was too great to make the journey.
The initial curiosity about the families who had what appeared to be a genetic version of Alzheimer's developed into a real study. Lopera, with Kenneth S. Cusick then at Harvard Medical School, Alison Goate of Washington University in St. Louis and other researchers found in 1995 the exact location of the paisa mutation in a gene on chromosome 14.
The focus on disease prevention stems from the overwhelming rate of potential treatment failures in Alzheimer's patients. Of 413 clinical trials from 2002 to 2013, more than 99% failed. The few that have been approved by the authorities provide temporary relief from symptoms, but ultimately cannot prevent memory loss or loss of other cognitive abilities.
This failure has prompted drug companies and academic researchers to consider conducting clinical trials on healthy people. According to popular belief today, when the earliest symptoms of Alzheimer's appear, the nerve cells have already begun to die and connections between one brain cell and another no longer work. When memory problems begin to appear, there is no medicine that can save the patients from the disease.
The extended Colombian families are ideal for researching preventive treatments because they have 1,000 or more paisa carriers, which is a large enough pool of possible study participants to obtain statistically significant results in a clinical trial. And because the development of familial Alzheimer's is so predictable in this group, researchers can start giving a drug that might prevent the disease 10 to 15 years in advance.
These families gained enough publicity to attract the attention of researchers at the Banner Alzheimer's Institute in Phoenix, who in 2010 approached major pharmaceutical companies to persuade them to participate in prevention studies. The Banner Institute collaborated with Genentech and Antioquia University in an experiment testing the antibody crenezumab, which aims to bind and help remove the toxic segments of the beta-amyloid protein from the brain. The experiment was funded by more than 100 million dollars from Genentech, the Banner Alzheimer's Foundation and the American Institutes of Health.
Experiment
The trial, known as the Alzheimer's Prevention Initiative, is unusual in several ways. It is run outside the secure confines of a large medical facility in Boston or San Francisco. Both Lopera and the University of Antioquia lack experience in clinical studies of any kind, and needless to say in the application of protocols, which are still in development, to examine the ability of a drug to stop a disease, sometimes 15 years before symptoms appear. "For the most part, no one believes that we will be able to carry out such an ambitious project in Latin America," says Lopera. The Banner Institute "believes in us, which is a great luck because we have shown that we can work with them seriously. And this project started successfully thanks to this trust."
In late 2013, the research group began giving the drug to the study participants, most of them people in their 30s and 40s. The researchers are still recruiting more participants, but the goal is to deliver the drug subcutaneously to 100 carriers of the Paisa mutation. (There are also two groups of placebo drugs, one of 100 carriers and one of 100 non-carriers.) Each patient will be monitored for five years. Brain scans and lumbar punctures will determine whether the drug has stopped the accumulation of beta-amyloid. Psychological tests will detect cognitive decline.
If crenzumab changes the course of the disease, it will create a breakthrough in the treatment of Alzheimer's. Further studies will then be able to determine whether the drug is effective in healthy elderly people who do not carry the Paisa mutation but whose brain scans show pathological changes that have only recently begun to occur.
The long-term relationships that Lopera and his colleagues cultivated with the 26 affected families over the decades were the key to recruiting patients for the trial. Lopera, with his long gray hair parted in the middle, creates an atmosphere of a benevolent uncle in his interactions with the families. In November 2014, when he heard that some journalists visiting Medellin planned to publish the last names of patients they met, he strongly opposed it, even though they had received permission. Lopera explained that the publicity may put a stain on the families, even on those who do not carry the mutation. Family members may have difficulty getting insurance or getting married.
The Colombian families, who remember generations of sick relatives, warmly embraced the clinical trial. Shinz Soliman, director of research at Genentech, predicts that even though many of the trial participants have to travel long distances to the hospital, they will come to receive the shots more regularly than average participants in studies conducted in the US or Europe.
This advocacy of hers is further strengthened thanks to Antioquia residents such as 40-year-old Hugo, who worked last November as a horse handler for wealthy people in the town of El Retiro. Once every two weeks, Hugo travels 32 kilometers to the state to receive his treatment: an injection of crenzumab or a placebo. Neither he nor the medical staff member giving the shot knows what he is getting.
Even if he turns out to be in the placebo group, Hugo says he understands why these clinical trials are important. His father and grandfather died of Alzheimer's, and four of his uncles, two of whom have already passed away, suffered from the disease. Hugo remembers how his father, from the moment he fell ill, compulsively polished the shoes of the family members all day and became very anxious if he did not see his wife even for a second. "It's hard," says Hugo. "This is a legacy that comes from the distant past, and we have to deal with it."
The experiments provide a glimmer of hope for Hugo and his relatives. "We feel good because, with Dr. Lopera, we hope there will be a positive result for these treatments and maybe there will be a cure for our children." Hugo says as he sits on a bench in the picnic area by the stables. Dogs bark loudly. He links an arm with one of his nieces, who links her arm with her sister's next to her.
Despite the distressing family medical history, Hugo and other family members gathered together on a gray day in November demonstrate great mental health. They tease each other about forgetting small details, and how this may indicate the onset of the disease. I ask Hugo's sister, Gudiala, 47, who is also participating in the experiment, if she is worried that she is going crazy. "Actually no," she says without hesitation. "The one who needs to worry is the one who will take care of me," and her answer provokes waves of laughter.
Only in 2018 will it begin to become clear whether the Colombian experiment helps people carrying the Paisa mutation, and the experiment itself will end in 2021. There is no guarantee that crenzumab will work. The drug failed in a US clinical trial conducted on people with mild to moderate Alzheimer's in 2014. Further analysis of the results revealed that the drug was of little benefit, apparently, in the early stages of the disease. For this very reason, researchers are promoting the Colombian trial to determine what will happen if the drug is given long before the first symptoms appear.
Even if Cranzumab fails in Colombia, all is not lost. The experiment is the best test yet of the 30-year-old beta-amyloid hypothesis. The hypothesis claims that toxic sections of the protein are the cause of the pathology of Alzheimer's disease. If the research does not bring any benefit to Hugo, Godella and others among the 26 families, and if other prevention studies now starting in the US also fail, science will have to turn its attention to other possible alternatives to the beta-amyloid hypothesis. Scientists may need to test drugs that prevent the accumulation of other toxic proteins, or they may need to test substances that protect nerve cells or interfere with the biochemical processes that underlie brain inflammation.
And even then, the infrastructures built in Medellin to conduct clinical trials on crenzumab may also be used to test the ability of the new approaches to prevent the disease. The ability to predict when it will erupt in patients carrying the paisa mutation may continue to be valuable to drug researchers in future studies. Medan is now becoming a major international center for Alzheimer's research, and may aspire to a site where significant breakthroughs will occur, a status that may remain for many years.
The city has the staying power required for the long experiments because the social structure of the families, and the common madness among the parents, grandparents and uncles and aunts, will probably attract participants to the clinical studies. More than that, family members naturally tend to take care of patients, unlike the impersonal medicine common in the US and Europe. Hugo remembers how he took short walks along the street with his father and how he held his hand so he wouldn't get lost and wouldn't find his way home.
The close family structure ensures that a rural laborer, often accompanied by relatives, will religiously arrive at the hospital every two weeks to receive medicine or have a brain scan. The curse of the conquistadors could become a blessing in disguise for significant medical progress that could benefit millions of people around the world who will receive the terrifying diagnosis.
in brief
- A Colombian neurologist located 26 extended families with a rare genetic form of Alzheimer's, most of them from rural areas around Medellin.
- The size of the group, more than 1,000 carriers of a mutation that makes all its carriers sick, makes it ideal for innovative clinical research.
- The participants of the study, conducted in Medellin, receive an experimental drug, in some cases 15 years before the expected outbreak of the madness.
- Success in research aimed at preventing the disease, rather than treating it after diagnosis, could dramatically change the development of Alzheimer's drugs.
More on the subject
Phoenix: Vision of Shared Prevention Trials Lures Pharma to Table, Part 1. Gabrielle Strobel in Alzforum. Published online February 25, 2010. www.alzforum.org/news/conference-coverage/phoenix-vision-shared-prevention-trials-lures-pharma-table
Alzheimer's Prevention Initiative: A Plan to Accelerate the Evaluation of Presymptomatic Treatments. Eric M. Reiman et al. in Journal of Alzheimer's Disease, Vol. 26, Supplement no. 3, pages 321-329; October 2011.
Origin of the PSEN1 E280A Mutation Causing Early-Onset Alzheimer's Disease. Matthew A. Lalli et al. in Alzheimer's & Dementia, Vol. 10, no. 5, Supplement, pages S277-S283; October 2014.
Alzheimer's: delay the decline of the screen, Gary Stix, Scientific American Israel, October-November 2010, page 50.
