Comprehensive Analysis of Genetic Contributions to Alzheimer’s Disease and Frontotemporal Dementia in Admixed Latin American Populations
Authors: Acosta‐Uribe Juliana , Escudero Stefanie Danielle Pina , Cochran J. Nicholas , Taylor Jared W , Solsberg Caroline Warly , Matallana Diana , Takada Leonel Tadao , Bruno Martin Alejandro , Levine Alexandra R. , George Dawwod S. , Lopera Francisco , Chonchol Andrea Slachevsky , Behrens María Isabel , Funes José Alberto Ávila , Zapata‐Restrepo Lina Maria , Brusco Luis Ignacio , Custodio Nilton , Franco Teresita Ramos , Bruna Bárbara , Ponce Daniela P , Gelvez Nancy , Lopez Greizy , Gomez Luisa , Buitrago Carlos Felipe , Reyes Pablo A , Durón Dafne Estefania , Pantazis Caroline , Maito Marcelo Adrian , Javandel Shireen , Godoy Maria Eugenia , Millon Maria Beatriz Bistue , Vitale Dan , Nalls Mike A , Singleton Andrew , Miller Bruce L. , Ibáñez Agustín , Kosik Kenneth S. , Yokoyama Jennifer S. , Montesinos Rosa , Resende Elisa de Paula França ,   Multi‐Partner Consortium to Expand Dementia Research in Latin America (ReDLat)
Published: January 2025

Background

Most research initiatives have emerged from high‐income countries (HIC), leaving a gap in understanding the disease’s genetic basis in diverse populations like those in Latin American countries (LAC). ReDLat tackles this gap, focusing on LAC’s unique genetics and socioeconomic factors to identify specific Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) risk factors in Mexico, Colombia, Peru, Chile, Argentina, and Brazil.

Method

We employed a comprehensive genetic analysis approach, integrating Whole Genome Sequencing (WGS), Exome Sequencing, and SNP arrays to understand the cohort’s unique genetic architecture. We conducted ancestry analysis and searched for disease‐causing variants with mendelian inheritance, genome‐wide association studies (GWAS), rare variant enrichment, and evaluation of Polygenic Risk Scores (PRS).

Results

We recruited and genotyped an initial cohort of 1046 participants with AD, 423 with FTD, and 855 healthy controls (HC) between 2020 and 2023. Analysis is ongoing, and we expect to sequence ∼600 additional samples in the coming months. Ancestry analysis revealed tri‐continental admixture, except for Brazil, which showed an additional Asian component (Figure 1). Top candidate gene rare variant enrichment associations (SKAT p < 0.05) were TREM2 for FTD and ABCA7 and ABCA1 for AD. GWAS identified a robust association with the APOE locus on chromosome 19 in AD vs. HC.. We tested an AD PRS developed in European populations by Bellenguez et al (2020). on our cohort using 83 single‐nucleotide polymorphisms.. The PRS modestly distinguishes between all patients and HC (p = 2.4 × 10^‐12), AD vs. HC (p = 2.2 × 10^‐12), and even FTD vs. HC (p = 4.3 × 10^‐5), albeit with modest separation between groups, as expected for its application in a genetically admixed population.

Conclusion

Our findings represent a pivotal step in understanding the genetic landscape of AD and FTD in admixed populations. They underscore the importance of including diverse populations in genetic research, paving the way for future studies. These findings have the potential to inform more personalized approaches to the diagnosis and treatment of neurodegenerative diseases in diverse global populations, as well as identify novel targets for therapeutic development.