Unraveling the high incidence of dementia in Latin America

By: Sarah Sharman, PhD, Science writer 

Globally, Alzheimer’s disease and other dementias affect about 55 million people, with nearly 10 million new cases diagnosed yearly. This number is predicted to double every 20 years, reaching 139 million by 2050, making the need for preventative measures and better diagnostic tools critical. Studies show that significant damage to the brain has already occurred by the time individuals show signs of dementia. As such, available treatments show little benefit for individuals already impaired with dementia. 

Preventative dementia research is complicated by the difficulty of finding the appropriate participant base. Participants should be people guaranteed, or highly likely, to develop dementia–a population that is hard to identify because the cause of most common types of Alzheimer’s disease is largely unknown. A rare subtype of Alzheimer’s disease, called autosomal dominant Alzheimer’s disease (ADAD), presents a unique opportunity for researchers because several genetic causes are identified for the disease, and mutation carriers always develop the disease at roughly the same age range.

One family in Antioquia, Colombia, with a long history of ADAD, became a key cohort for Alzheimer’s disease research, serving as the subject of dozens of studies and one clinical trial. The dementia field is learning a lot about the cause and progression of this devastating disease from this family. In return, they received an answer to their decades-long question about why so many family members were suffering from, and ultimately dying from, this devastating disease. HudsonAlpha faculty investigators Rick Myers, PhD, and Nick Cochran, PhD, are part of the ongoing efforts to understand the dynamics of dementia by studying families in Latin America overburdened by the disease. 

How a Colombian family found answers while giving back to Alzheimer’s disease research 

Several decades ago, a neurologist named Francisco Lopera began studying the family in Antioquia because of their high incidence of very early onset Alzheimer’s disease. On average, the disease strikes individuals in this family in their mid-40s and results in death within 10 to 12 years. To date, more than 6,000 individuals from 26 extended families are enrolled in the study. By analyzing the individuals’ genomes, researchers discovered that many carry a rare genetic mutation for early-onset Alzheimer’s disease in a gene called Presenilin-1 (PSEN1). The mutation is referred to as PSEN1 E280A after the mutation’s location on the gene. 

Other Colombian families, unrelated to the Antioquia family, were also found to have high incidences of early-onset Alzheimer’s disease. Many of these families were from small, isolated towns like Antioquia. Small towns and villages in rural Colombia are often genetically isolated, meaning there is little genetic diversity because of a lack of immigration into the area. This creates the perfect environment for amplifying rare mutations, like the PSEN1 mutation. 

A recent publication confirmed the role of ancestry and genetic isolation in the mutational landscape of dementia in Colombia. A group of researchers, including Drs. Cochran and Myers, analyzed the genomes of 900 Colombian individuals with or without various dementias for deleterious variants in disease-causing and risk-conferring genes and examined participants’ global and local ancestry proportions.  

Through these analyses, researchers identified 21 pathogenic variants in Alzheimer’s disease- and frontotemporal lobar degeneration-motor neuron disease-related genes. PSEN1 harbored the most variants. Unique variants from three continental ancestries– African, European, and Native American– were identified. The results show the significant role that demographic history plays in shaping a population’s genetic risk for disease and emphasize the importance of inclusiveness in genetic studies. 

The age of onset of dementia is likely linked to genetic factors 

Ongoing studies focusing on the Antioquia family are trying to unravel the mysteries behind the age of onset of dementia. Most individuals in the large Colombian family carrying the PSEN1 E280A mutation develop mild cognitive impairment (MCI) at a median age of 44 and dementia at age 49, although some individuals have been reported to develop MCI nearly three decades after their family’s median age. The predictable age of onset and existence of rare outliers make this family a valuable source of potential genetic variants that delay the onset of Alzheimer’s disease. 

Dr. Cochran and his lab, along with collaborators at the University of California, Santa Barbara, Universidad de Antioquia, Icahn School of Medicine at Mt. Sinai, and Washington University in St. Louis, were part of a recent study that analyzed the genomes of 340 individuals from the Antioquia family to gain insight into the genetic landscape of age of disease onset. The research team identified several gene candidates that are likely involved in Alzheimer’s disease age of onset, although further studies with more individuals are necessary for confirmation. One promising hit was a new variant in the gene CLU, previously implicated as a genetic risk factor for late-onset Alzheimer’s disease. 

While the Antioquia family is the largest known dominant Alzheimer’s disease family, they still represent a small group for statistical purposes. Recruitment of more patients with early-onset dementias from South American countries will help overcome this limitation in future studies. One such effort to increase Latin American representation in genetic research is Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat). The multinational effort, which includes Dr. Cochran and his lab, seeks to expand dementia research in Latin America, focusing especially on underserved and diverse populations. 

The consortium aims to identify the unique genetic and socioeconomic determinants of health that drive Alzheimer’s disease and other dementias in Latin America. The five-year project aims to collect neuroimaging, genetic and behavioral data on over 4,000 individuals from Argentina, Brazil, Chile, Columbia, Mexico, Peru, and the U.S. to offer a unique understanding of the genetic and environmental underpinnings of dementia.

This story was originally published in the 2021-2022 HudsonAlpha Research Report. Click here to view the original story and other research stories from the report.