A Country Doctor, But Oh So Much More: Francisco Lopera, 73

On Tuesday September 10, Francisco Lopera died of cancer at his home in Medellin, Colombia. He was 73, and only just beginning to see his life’s work come to fruition.

In fact, Lopera still had much to do. With his group, he was gearing up for a second Alzheimer’s disease prevention trial—chasing an antibody known to remove plaques with a small molecule intended to keep them from returning—in the people to whom he had devoted his life’s work.

Francisco Lopera. [ Courtesy of the Consorcio de América Latina y el Caribe sobre la Demencia (LAC-CD).]

As a young country doctor in the early 1980s, Lopera realized that the villages in the mountainous Paisa region around Medellin where he had grown up were home to families beset with a heritable form of early onset dementia. Since then, Lopera focused his clinical work and his research on these families and their disease. The result? In large part, the Alzheimer’s Prevention Initiative. The API, together with its cousin, the Dominantly Inherited Alzheimer’s Network (DIAN), has pioneered therapeutic intervention trials founded on large-scale human data gleaned from decades-long clinical and biomarker studies of deeply phenotyped cohorts.

This description hardly reflects the effort involved. Early on, Lopera and colleagues traced afflicted families and their genealogies, building pedigrees that pointed to a founder mutation in the 18th century. Lopera forged international collaborations with Ken Kosik, Alison Goate, and Cindy Lemere, and, in the 1990s, co-authored seminal papers on the presenilin 1 gene and the E280A mutation that caused autosomal-dominant Alzheimer’s disease, named Paisa after its origin region (Alzheimer's Disease Collaborative Group et al., 1995; Lemere et al., 1996; Lendon et al., 1997; Lopera et al., 1997).

Grupo Neurociencias de Antioquia, aka GNA. [Courtesy of Group of Neuroscience.]

By and by, Lopera built the interdisciplinary Grupo Neurociencias de Antioquia at the University of Antioquia in Medellin. By the late 2000s, Lopera, with many colleagues, students and mentees, had collected information on, and built clinical care for and research relationships with, a thousand members of this kindred.

This was the largest Alzheimer’s kindred known at the time, but it was only a start. When in 2008 Lopera met Eric Reiman, Banner Alzheimer’s Institute in Phoenix, the two joined forces with Banner’s Pierre Tariot and Jessica Langbaum to make prevention trials a reality. For that, the Colombian API registry needed to grow, and now, in 2024, it contains 6,000 kindred members from age 7 to the late 70s, of whom 1,200 carry the mutation that leads to MCI at around age 44, and dementia by 49.

Lopera embraced Reiman’s idea of working to help his families in a way that would help AD patients across the world. When Reiman and U.S. colleagues visited Colombia in 2008, Lopera introduced them to a gathering of 700 family members and took them to visit affected families in their homes. “It was a life-changing experience,” Reiman recalled.

In 2009 and in 2010, the API scientists convened leading AD researchers, funders, FDA regulators, drug developers, and others to persuade them that the time had come, and the tools were in place, to start FDA license-enabling trials of the most promising investigational drugs in cognitively normal people whose genetics and biomarker profiles put them within five years or so of developing Alzheimer’s symptoms (Feb 2010 news series). Until then, leaders in the field had been paying lip service to this idea, calling it premature. At these gatherings, the pendulum swung toward action. “At the end, we went around the table, asking each participant for their concluding thoughts. Francisco was the last person to speak. When it was his turn, he simply said ‘My families are waiting,’ and everyone understood,” Reiman wrote in a 2023 letter recommending Lopera for the Potamkin Prize, which he won in 2024 (Mar 2010 conference news).

Francisco Lopera ringed by microphones and cameras at a GNA media event. Yakeel Quiroz, MGH, in red jacket on right. [Courtesy of Pierre Tariot.]

By 2011, API was in full gear, planning in detail for trials, bringing in more expertise. Media companies had caught on and were flocking to Medellin. In 2012, then-NIH director Francis Collins announced federal funding for API’s Colombia trial as part of the U.S. National Plan to Address Alzheimer’s (March 2011 news series; May 2012 news).

This trial evaluated Roche/Genentech’s antibody crenezumab. Together with DIAN’s trial of gantenerumab and solanezumab, these were the first prevention studies of disease-modifying drug candidates. Both missed their primary endpoint. In 2022, Lopera had to tell “his” families that there was still no drug that could forestall their family scourge (see Jennie Erin Smith’s profile in The New York Times).

Francisco Lopera was known for his love of dancing. [Courtesy of Pierre Tariot.]

That said, Lopera and many other scientists and drug developers considered the trial valuable preparation for the next one waiting in the wings. Much had been achieved. For this initial trial, the University of Antioquia’s first cyclotron, PET system with amyloid and tau ligands, and 3Tesla MRI were installed. For up to eight years, 254 middle-aged, working Colombians traveled sometimes significant distances for frequent assessments and dosing, including through COVID and occasional violence encountered en route. Despite it all, 94 percent completed the trial, a far higher rate than AD trials typically achieve elsewhere.

The trial validated innovative design features for future prevention studies. It included noncarriers for comparison and to obviate the need for genetic disclosure. It recorded the trajectory of blood-based and CSF biomarkers, and MRI and PET imaging, prior to the onset of a person’s symptoms. This information informs the next trial, which Lopera was hoping to announce this year. “His” families, after all, are still waiting.

As is the case for DIAN, ongoing biomarker research in the larger observational cohort has generated finding after finding. To cite but one, it found that the neurodegeneration marker neurofilament light starts changing in the blood of E280A carriers as early as 22 years prior to symptoms, in people’s 20s (Quiroz et al., 2020).

In the minds of his peers and the public, Lopera’s contribution to science is bound up in his work with the E280A kindred. Lesser known is that, in the course of attracting thousands of people in Colombia for dementia care over 40 years, the GNA has also identified and characterized members of genetic kindreds suffering from other forms of ADAD, as well as from frontotemporal dementia, and the vascular dementia called cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, aka CADASIL.

Did you know Francisco Lopera? What did he mean to you? What did this obituary leave out? For the comfort of his family and friends in Colombia and elsewhere, and to teach the many young scientists joining the field these days, share a memory, a vignette, an image. Email gstrobel@alzforum.org or type into the comment field below.—Gabrielle Strobel

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References

Mutations Citations

  1. PSEN1 E280A (Paisa)

News Citations

  1. Phoenix: Vision of Shared Prevention Trials Lures Pharma to Table
  2. Phoenix: Trials in Colombia and the U.S. for Those at Highest Risk?
  3. Colombians Come to Fore in Alzheimer’s Research, Mass Media
  4. NIH Director Announces $100M Prevention Trial of Genentech Antibody

Therapeutics Citations

  1. Crenezumab

Paper Citations

  1. Alzheimer's Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  2. Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, Yamaguchi H, Ruiz A, Martinez A, Madrigal L, Hincapie L, Arango JC, Anthony DC, Koo EH, Goate AM, Selkoe DJ, Arango JC. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996 Oct;2(10):1146-50. PubMed.
  3. Lendon CL, Martinez A, Behrens IM, Kosik KS, Madrigal L, Norton J, Neuman R, Myers A, Busfield F, Wragg M, Arcos M, Arango Viana JC, Ossa J, Ruiz A, Goate AM, Lopera F. E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat. 1997;10(3):186-95. PubMed.
  4. Lopera F, Ardilla A, Martínez A, Madrigal L, Arango-Viana JC, Lemere CA, Arango-Lasprilla JC, Hincapíe L, Arcos-Burgos M, Ossa JE, Behrens IM, Norton J, Lendon C, Goate AM, Ruiz-Linares A, Rosselli M, Kosik KS. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9. PubMed.
  5. Quiroz YT, Zetterberg H, Reiman EM, Chen Y, Su Y, Fox-Fuller JT, Garcia G, Villegas A, Sepulveda-Falla D, Villada M, Arboleda-Velasquez JF, Guzmán-Vélez E, Vila-Castelar C, Gordon BA, Schultz SA, Protas HD, Ghisays V, Giraldo M, Tirado V, Baena A, Munoz C, Rios-Romenets S, Tariot PN, Blennow K, Lopera F. Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study. Lancet Neurol. 2020 Jun;19(6):513-521. Epub 2020 May 26 PubMed.

External Citations

  1. The New York Times

Further Reading

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