Remembering Francisco Lopera: A pioneer in the study of familial Alzheimer disease

The recent passing of Francisco Lopera on September 10, 2024, at the age of 73, marks a profound loss for the neurologic community. Lopera, a Colombian neurologist who dedicated much of his career to the study of familial Alzheimer disease, was renowned for his pioneering work with a large extended family in Colombia that harbors a genetic mutation leading to early-onset Alzheimer disease.

His research has been instrumental in advancing our understanding of the disease and has provided valuable insights that may help prevent or delay its onset in future generations. Lopera's contributions have not only shaped the course of Alzheimer disease research but also offered hope for new preventive approaches in the fight against this devastating condition.

The discovery of familial Alzheimer disease in Colombia

Lopera’s groundbreaking research began in the 1980s when he first encountered an extended family in Medellín, Colombia, who exhibited a striking pattern of early-onset dementia. The family, known as the “paisa” kindred, comprises over 6,000 members, many of whom carry the Presenilin 1 (PSEN1) mutation. This mutation, which leads to the accumulation of amyloid plaques in the brain, causes Alzheimer disease symptoms to appear as early as age 40, with some individuals developing the disease even younger.

At the time, little was known about the genetic basis of early-onset Alzheimer disease, particularly in populations outside of the United States and Europe. Lopera’s meticulous work in documenting the clinical history of this family and tracing the genetic roots of the disease led to the identification of the PSEN1 E280A mutation, one of the most aggressive forms of familial Alzheimer disease and now a focal point for global Alzheimer disease research.

The Colombian Alzheimer’s Prevention Initiative

Lopera’s work extended beyond the identification of the genetic mutation. Recognizing the significance of this family’s genetic profile, he became a key figure in the Alzheimer’s Prevention Initiative (API) clinical trial, a large-scale international research effort aimed at finding preventive treatments for Alzheimer disease. The Colombian cohort of the API, launched in collaboration with researchers from the United States and Europe, was unique in its ability to study a population with a high risk of developing Alzheimer disease at a young age.

This cohort allowed researchers to investigate not just the genetic mechanisms underlying Alzheimer disease but also to test preventive treatments in individuals who were genetically predisposed to the disease but had not yet shown symptoms. One of the key studies involved an experimental drug that targeted amyloid buildup, aiming to prevent or delay the onset of cognitive decline in mutation carriers. This type of pre-symptomatic intervention holds promise for delaying Alzheimer disease progression and has the potential to reshape therapeutic approaches for both familial and sporadic forms of the disease.

The discovery of protective factors

Among Lopera’s most fascinating contributions was the discovery of individuals who carried the PSEN1 mutation but did not develop symptoms at the expected age. One case, in particular, garnered international attention: a woman in her 70s who had the mutation but showed only mild cognitive impairment despite the presence of extensive amyloid plaques in her brain. This individual was found to carry an additional mutation in the APOE3 Christchurch variant, which may have protected her from the full onset of Alzheimer disease symptoms. (https://www.nih.gov/news-events/nih-research-matters/gene-variation-may-protect-against-alzheimers-disease) This discovery could have profound implications for the development of treatments aimed at enhancing protective factors in at-risk populations.

Francisco Lopera’s legacy

Francisco Lopera leaves behind an enduring legacy that spans multiple dimensions of Alzheimer disease research:

1. Advancing our understanding of familial Alzheimer disease. Lopera’s identification and study of the Colombian kindred has provided invaluable insights into the genetic underpinnings of early-onset hereditary Alzheimer disease. His work laid the groundwork for understanding how specific mutations, such as PSEN1, contribute to the disease, offering a window into the biological processes that drive Alzheimer disease pathology.
2. Pioneering Alzheimer disease prevention research. Lopera’s involvement in the API and other preventive research initiatives has shifted the focus from treating Alzheimer disease after symptoms appear to preventing cognitive decline in high-risk individuals. His work has highlighted the potential for early intervention, particularly in genetically predisposed populations, to delay or prevent the onset of symptoms.
3. Discovering protective genetic factors. Lopera’s documentation of individuals who resisted the effects of the PSEN1 mutation, despite carrying the gene, opened new avenues for research into genetic and biological protective factors. His work in identifying the APOE3 Christchurch variant as a possible protective mutation may one day lead to the development of treatments that mimic these protective effects, benefiting a broader population of patients with Alzheimer disease.
4. Building a research legacy in Colombia. Lopera’s dedication to the study of Alzheimer disease in Colombia helped put the country on the map as a hub for Alzheimer disease research. He created a research environment that fostered international collaboration, while also training a new generation of Colombian scientists and neurologists who continue his work today.

A lasting impact on neurology

Francisco Lopera’s passing is a significant loss for the global neurology community, but his contributions will continue to resonate. His work fundamentally changed the way we think about Alzheimer disease—particularly the genetic, biological, and preventive aspects of the condition. His studies on the paisa kindred not only advanced our understanding of familial Alzheimer disease but laid the groundwork for exploring new treatments, prevention strategies, and genetic discoveries in the quest to better understand and ultimately conquer Alzheimer disease.

Lopera’s life’s work represented the ultimate scientific dedication: his desire to uncover the unknown, his persistence to follow challenging research questions, and his deep empathy for patients and families in his community affected by neurodegenerative disease. Dr. Lopera’s contributions to Alzheimer research will continue to guide our efforts in understanding and combating this devastating disease for decades to come.

*Francisco Lopera was the original author of MedLink Neurology’s Familial Alzheimer disease article in 2006, and he continued to update the article until a successor assumed authorship in 2023.

Further reading about Dr. Lopera’s life and contributions to Alzheimer disease research:
AlzForum: A Country Doctor, But Oh So Much More: Francisco Lopera, 73

MedLink acknowledges the use of ChatGPT-4, an Artificial Intelligence chatbot, in drafting this blog entry.

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