Hugo, a participant in a pioneering Colombian drug trial, along with two nieces, Mariana and Daniela.

A Colombian university is providing regular workshops on brain basics and genetics to grade schoolers from families who face a high risk of developing Alzheimer’s in the prime of life from a rare genetic mutation. The “talleres” set up by the University of Antioquia in Medellin attempt to prepare these youngsters for the all-too-frequent possibility of a mother or father starting to lose their memories just before the age of 50, marking the beginning of a relentless decline that results in their deaths 10 years or so later.

In the course of these educational sessions, the youngsters also learn the unsettling information that they, too, risk becoming the next generation of patients. The Colombian department of Antioquia has the largest group in the world of relatives at risk for familial Alzheimer’s. In this form of the disease, inheritance of a genetic mutation from even one parent means that a person is virtually destined to get Alzheimer’s at an early age. The so-called paisa genetic mutation—nicknamed for the people of Antioquia and surrounding areas—changes the way a particular protein regulates the functioning of an enzyme in brain cells, precipitating the buildup of toxic amyloid-beta protein fragments.

Francisco Lopera, a neurologist at the University of Antioquia contends that informing eight or nine-year olds of their genetic histories is essential to keep families intact and assist children in helping their parents when they become ill. In a radical role reversal, a child before the age of 10 may end up becoming the primary caregiver— un nino cuidador—if a parent develops Alzheimer’s. Lucia Madrigal, a nurse and psychologist who has worked with these families for decades, teaches children in these workshops. "We explain how they can help in caring for the sick without leaving aside their childhood," she says.

Lopera first came across members of these families in the environs of Medellin in the early 1980s. He and other research collaborators later traced the origins of the mutation to a person, likely of Spanish origin, in whom the genetic alteration arose spontaneously during the 1600s when Colombia was being colonized. The University of Antioquia has gained international renown because it has become the site of an innovative drug trial intended to prevent the disease before symptoms appear in this group of families.

The workshops, also given to older youths, were initiated because of the realization that a diagnosis may rip apart family ties. “The situation with Alzheimer’s at the center of a family can be catastrophic,” Lopera says, adding: “A child doesn’t understand what’s happening with the mother or father who is affected.” A parent who becomes belligerent, a not infrequent symptom, may be cast out. “We have situations where the family slammed the door of the house on the father because he became aggressive and they didn’t understand that he was sick”

In educating these youngsters to better cope, Lopera and his team try to instill an understanding that the disease can be explained through brain science. When Lopera first started the epidemiological sleuthing that led to the identification of the paisa mutation, family members often believed that the illness resulted from witchcraft or touching a manzanillo tree, which causes skin irritations and bears poisonous fruit.

In the workshops, Lopera and his colleagues provide simple explanations of neurobiology to youngsters who attend the workshops, showing them samples from the 233 donations in the university’s brain bank from members of the the paisa mutation group. These sessions, which do not yet include genetic testing, involve a simplified discussion of what a chromosome is and how inheriting a single mutation from either the mother or father will lead to the disease. “They discuss whether some day in a not too distant future when we have a formal program of genetic counseling whether they would like to know whether or not they are carriers of the mutation,” Lopera says.

The University of Antioquia has for several years attracted attention as the site of one of the most innovative clinical trials in biomedicine. The number of paisa families touched by this early onset form of Alzheimer’s—26 extended families encompassing more than 5,000 potentially at-risk individuals—makes it an ideal population for testing novel Alzheimer’s therapies.

After a multitude of drug failures, researchers want to prevent the disease rather than treat symptoms of cognitive decline once they arise. A number of clinical trials—the one in Colombia being the first—are starting to assess the effectiveness of drugs that counter amyloid-beta 10 years or more before cognitive symptoms appear. These trials are based on the premise that, once symptoms appear, any drug that neutralizes or rids the brain of amyloid detritus may intervene too late in the disease process to be effective.

Familial Alzheimer's makes up less than one percent of the more than 35 million cases worldwide. Genes can also increase the chances of developing the more common form of Alzheimer’s past the age of 65. But these susceptibility genes do not guarantee that an individual will develop the disease, as does the paisa mutation.

The number of the families in Antioquia—and the ability to predict the age when they will start to show symptoms—means that researchers can use brain scans and other technologies, as well as psychological testing, to tell whether a drug is altering amyloid buildup and preserving cognition years before the onset of the illness. The first patients in the clinical trial began receiving an anti-amyloid drug, crenezumab, a year ago.

Lopera and researchers from the Banner Alzheimer’s Institute in Phoenix, which is conducting the $100 million Colombia trial along with Genentech, (with backing as well furnished by the U.S. National Institutes of Health), held a press conference in early November in Medellin to help recruit 70 additional trial participants needed to complete full enrollment of 300 participants. To achieve this goal, Lopera estimates that that they will need to inscribe some 2400 more family members in a registry the university maintains. Each participant must conform to an extensive list of criteria—age, literacy and other factors—to be eligible for the trial.

Most Alzheimer’s drugs have failed—and crenezumab, the anti-amyloid agent undergoing testing in the Colombia trial—has also experienced setbacks. Last summer, Genentech, along with its partner AC Immune, announced results of a mid-stage trial that showed the drug did not meet is primary goals—“endpoints” in clinicalese—of slowing cognitive decline in patients with mild to moderate forms of the disease.

The drug did appear to have a beneficial effect in patients with mild Alzheimer’s at a high dose. That may possibly hint that the rationale for the Colombian trial—stopping disease pathology years before symptoms appear when amyloid-beta is wreaking most of its damage—may have some justification. The trial is also intended as a test of the amyloid hypothesis. If the Colombian trial, and a few others using anti-amyloid drugs in pre-symptomatic patients, do not succeed, researchers may have to look for another biological target to treat Alzheimer’s.

The trial also illustrates the payoffs of going outside traditional circles to conduct clinical trials. Lopera and his colleagues at the University of Antioquia have tracked the 26 families closely and meticulously assembled genealogies. They have also assisted in identifying the paisa mutation, more formally known as E280A, in a gene known as Presenilin-1.

The trial families live both in Medellin and its surroundings, areas touched by the decades-long struggles among left-wing guerrillas, the national government and para-military groups. Eric Reiman, a scientist from Banner Alzheimer’s Institute who has been instrumental in organizing the Colombian trial along with his Banner co-leader Pierre Tariot, remembers going to Yarumal, a municipality north of Medellin, in a military convoy during the late 2000s. The level of violence has subsided since then.

Meanwhile, Lopera, with his bushy eyebrows and long, grey hair parted in the middle, remains an avuncular presence among the families, someone fiercely protective of their well-being. The neurologist spent part of his youth growing up in Yarumal and remembers neighbors who developed la bobera. Lopera was adamant with three U.S. journalists invited to Medellin for a press briefing that they should not use surnames of study participants in their stories, even when some family members had agreed unreservedly to fully identify themselves.

Revealing the names, in Lopera's view, could stigmatize, not just the individual family members, but anyone else with that surname who is looking for a marriage partner or trying to buy insurance. The continuing closeness to the people of the region will be essential in recruiting additional trial participants and overseeing the study's long trajectory as trial participants make the trek to Medellin every two weeks to receive either crenezumab or a placebo over the five-year course of the study.

Image Source: Gary Stix