In 1982 Dr Francisco Lopera was working at Medellin’s University of Antioquia in Colombia when he had a curious encounter. In his neurology clinic he met a man aged only 47, who displayed dementia symptoms similar to Alzheimer’s disease. This was very unusual, because only 5% of people who develop Alzheimer’s are known to do so before the age of 65. Upon questioning the man, Dr Lopera found out that his grandfather, father, and several brothers also had dementia. Three generations of the family were affected, and in each generation half of the children were affected, a clear pattern indicating that this condition was hereditary. This curious discovery led Dr Lopera to investigate further, and over the next decade he identified the largest known family with inherited Alzheimer’s disease who were currently living in the region of Antioquia. By the end of the 1980s, the researchers had traced the family tree back over 300 years. What they found was a disease devastating for those affected: symptoms usually develop between the ages of 45 and 50, with an average age of onset of 47. However, some can experience symptoms as early as 32. Locals have termed this form of dementia “La Bobera”, which translates as the foolishness. To understand what it means to be affected by La Bobera, find out about the story of Magnolia and her family here.
Solving the puzzle
Dr Lopera and his team continued their research to identify the cause for this aggressive form of young-onset dementia. Eventually, with the help of researchers from the States, they discovered that there was one mutation responsible for this type of early onset Alzheimer’s disease: a mutation at E280A on chromosome 14. The gene affected is presenilin 1, which is involved in the process of producing the amyloid beta protein. The amyloid protein is known to aggregate and forms plaques in the brains of people with Alzheimer’s disease. There are around 5000 people in Yarumal and the surrounding state of Antioquia that carry this genetic mutation in presenilin 1. This makes Colombia home to the largest concentration of people who carry a genetic mutation that results in 100% of carriers developing Alzheimer’s disease. If one parent has the gene, then there is a 50% chance their child will have it, too. Interestingly, a few people will develop the condition later, and it has been shown that these individuals carry a different genetic variant that seems to provide some protection against the disease. This modifier gene can delay onset by as much as 8 to 10 years.
Through further investigations Dr Lopera and his team managed to identify that the mutation arose from a common ancestor around 375 years ago. It is thought that in the early 17th century a Spanish conquistador introduced the mutation to the Colombian region of Antioquia. Due to limited marriage option, intermarriage between distant cousins led to the mutation becoming more prominent within the families.
A glimpse of hope
For the families affected, the mutation has been devastating. Not only does it place an extremely high burden of care on the relatives of those affected, it also comes with the terrible knowledge that for half of them the disease is inevitable, and that the mutation will be passed on to half of their children. However, there is hope that a clinical trial may provide new treatments not only for those affected in Colombia, but for future dementia sufferers.
99% of clinical trials for Alzheimer’s disease are thought to fail because drugs are tested after the disease has taken hold. However, the hereditary pattern in this Colombian family means that we can predict which family members will get Alzheimer’s disease. Therefore, treatments can be administered before any symptoms occur. This creates the perfect setting for a ground-breaking new trial, where we can determine if preventative treatments can be successful. After some searching, Dr Lopera was able to find people willing to finance a trial in Colombia, and the trial is currently ongoing. An antibody directed against the amyloid protein is being tested. Although it is possible that the drug will inhibit the plaques formed by amyloid and the family will still get the dementia, the hope is that giving this drug preventatively, will lead to people carrying the genetic mutation not developing Alzheimer’s disease.
“If it makes a difference for them, I think there’s a reasonable chance it could make a difference for all the rest of the people who get Alzheimer’s disease,” -Professor Kawas.
Meanwhile, researchers are attempting to identify biomarkers that can be used to identify the disease process early on. A group of forty 18 to 25 year olds is being studied to see if brain changes appear in people that young. A new memory test that can catch symptoms early is also being tested. It appears that only remembering one characteristic of something is an early sign of disease onset. In this new memory test, a participant is being shown coloured shape and must recall both colour and shape. Previously, clinical trials have faced challenges such as mis-diagnosis, or attempting to treat people with advanced Alzheimer’s that may already have lost too many cells to respond to therapy. These are overcome by using this particular setting created by a genetic mutation. Other challenges such as measuring trial outcomes remain. It is difficult to directly measure or quantify changes in the way a person thinks (their cognition).
There are many challenges faced by those involved in carrying out research in Antioquia. The region is not entirely safe, and there are security threats by drug traffickers and rebels of the revolutionary armed forces of Colombia (FARC). Once a nurse was kidnapped by guerrillas while collecting samples in the Angostura village, and although she was subsequently released this highlights the security issues in the region. Furthermore, the population is relatively uneducated with many misconceptions about Alzheimer’s disease, such as that it can be transmitted by sexual activity. Family members take care of their relatives, but may often be overwhelmed by the task at hand. They can take desperate measures such as locking the person with dementia in a room to prevent them from wandering off. Due to the poverty in the region, those carrying out the trial have to provide basic care such as antibiotics, food and adult diapers. It proved difficult to find people willing to support a $50 million trial under these conditions. There is also the ethical issue of whether to inform the participants of the trial whether they are mutation carriers. This knowledge can be devastating and can result in drastic reactions by those affected, such as suicide. There is a lack of genetic counselling available in the region. Therefore, the researchers in the trial have opted to give all participants treatment, so that mutation carriers are not revealed. Placebos are given to non-carriers, and treatment or placebo is given to carriers. Given that the treatment is given to healthy people in their 20s and 30s, safety is of the highest priority. Despite all these issues, for the family the potential benefits far outweigh the risk of trialling unproven drugs.
“I am a little bit worried,” says Patricia. “But I want to participate: it’s for me, it’s for my family, and it’s for the rest of the world.”
Watch the CBS documentary titled “The Alzheimer’s Laboratory” to find out more about Dr Lopera’s research.