The Country Doctor Who Upended Our Understanding of Dementia

In 1978, Dr. Francisco Lopera did what recent medical school graduates in Colombia and much of Latin America have long done: He set out for an obligatory year of work in a remote part of the country, where an inexperienced médico rural might be the only physician for miles. Dr. Lopera, who was born in the Andean region of Antioquia and knew mostly mountains and farm life before medical school, carried out his service in the Darién Gap, on the Caribbean coast near Panama.

There Dr. Lopera, a groundbreaking Colombian Alzheimer’s researcher who died this week at age 73, treated stabbings, snakebites, complicated births, burns and fevers in a hospital that had electricity for only half the day. On one occasion, he was kidnapped by Marxist guerrillas. Another time, he had to flee gunshots.

When I met Dr. Lopera in 2017, to start research on a book about the families with Alzheimer’s that became his life’s work, he told me a story about two young brothers who had died one after the other in his hospital, of unknown causes. Lopera traveled to the family home in a remote jungle clearing, where he discovered that the boys’ surviving siblings had bites on their fingers from vampire bats. He sent the bodies to a pathology lab hours away by boat, and the pathologists confirmed rabies. When the government brought in a rabies expert to investigate, Dr. Lopera joined him.

He left that experience — long nights in the rainforest, searching for hidden roosts, engrossed in the natural history of rabies and bats — wanting to become a rabies epidemiologist. But that was not to be. His interests were eclectic and quick to change, and a few years later he became a neurology resident in Medellín.

In 1984, Dr. Lopera examined a farmer in his 40s who appeared to have dementia. Dr. Lopera took again the unusual step of traveling to the family home, in a mountain hamlet like the one where he had been born. Not just the farmer had symptoms of dementia, he saw — a brother also appeared to be affected. Dr. Lopera had discovered what would turn out to be the world’s largest family with early-onset Alzheimer’s disease. The family shared a genetic mutation, later nicknamed the paisa mutation, that was unique to their region of Colombia. Dr. Lopera spent the next four decades studying the family’s 6,000 members.

It is one thing to build a research cohort in a disease population, launch a hunt for an Alzheimer’s gene, start a bank of autopsy brains, conduct long-term studies in mutation carriers to understand the evolution of their disease and investigate therapies that might prevent or stall it. It is quite another thing to do all this with little money, in a country struggling with wave after wave of political and drug violence.

In the late 1980s, when Dr. Lopera’s work with the Colombian families was barely underway, his university was attacked by right-wing paramilitaries associated with drug traffickers; several of the victims were physicians. Two decades later, while recruiting participants for a landmark clinical trial of a therapy to prevent Alzheimer’s, Dr. Lopera and his colleagues still faced harassment, threats and kidnappings. The villages home to so many of his patients were deep in the clutches of guerrilla and paramilitary armies.

I ended up spending seven years in Medellín observing Dr. Lopera and the families with Alzheimer’s he studied. When I arrived, he was in his late 60s, with a disarming charm, a knack for forging productive alliances with investigators abroad, and a bedside manner that Kenneth Kosik, an American neurology researcher and longtime collaborator of Dr. Lopera, described as that of “a country doctor who still believed in the laying-on of hands.”

I loved watching Dr. Lopera conduct his grand rounds at the University of Antioquia, where he assessed people with Alzheimer’s and other neurodegenerative diseases in front of his students and colleagues. He engaged in a natural dialogue with patients, affable and unobtrusive; it was as if they were backslapping old friends at a country tavern. Yet he was collecting information that allowed him to diagnose dementia or assess its progress, with a precision few could match.

The people he studied were from long-suffering, typically poor families, with rural roots, who saw few prospects for a treatment or a cure. They knew, as he did, that only later generations would benefit from his efforts, and then only with luck. And yet they hung in with him — parents, children and grandchildren — for study after study, undergoing brain scans, blood draws, spinal taps and cognitive tests. Starting in 2013, hundreds enrolled in a clinical trial of an experimental antibody, called crenezumab, that it was hoped would stall or prevent their disease.

In 2019 the families learned of the extraordinary case of Aliria Piedrahita de Villegas, a Medellín woman who carried the dreaded paisa mutation but had made it to her middle 70s before developing symptoms of Alzheimer’s: a 30-year delay. That discovery, and the ongoing study of her genes and brain, broke open a new way of thinking about Alzheimer’s treatments, elucidating different genetic and cellular mechanisms from those long presumed to be involved.

But disappointment loomed. In the summer of 2022, Dr. Lopera learned that, for all the fanfare at its inception, the clinical trial of crenezumab had failed to show a benefit. Failures of Alzheimer’s drugs had become the norm worldwide, but that made it no easier on him or the families. Study participants and their loved ones filed into an auditorium at the University of Antioquia, as they had done regularly during the course of the decade-long trial, to hear from “el doctor.”

He was by then a less humble figure than in 1978. Even though the clinical trial had produced a negative result, its successful execution amid extremely trying circumstances had turned him into a darling of the Alzheimer’s research world. He was increasingly bathed in accolades, prizes, media attention and proposals. He didn’t get out into the countryside much.

On that Saturday morning in August 2022, however, Dr. Lopera was once again a country doctor, facing a room of country people. None of his foreign collaborators or drug-company sponsors accompanied him, just his longtime colleagues at his research group, the Grupo de Neurociencias de Antioquia, who wore matching black polo shirts and formed a receiving line, in a solemn display. As Dr. Lopera delivered the bad news in his gentle but frank style, some participants cried. The rest were done crying. Word of the results had already reached them through other channels, and perhaps came as no surprise. After 40 years of participating in clinical research, these families had learned to resist undue hope and resist despair.

As the day wore on the mood lifted. The university band played. Waiters served a hearty traditional lunch, and no one seemed in a hurry to leave. Dr. Lopera danced and danced with the trial participants. He was a fantastic dancer ever since his days as a young doctor in the Darién Gap. He danced to so many songs with so many partners that he was dripping with sweat by the late afternoon, looking about to collapse. I doubt there has ever been a clinical trial anywhere in the world that ended in such a way.