Genetic Contributions to Alzheimer’s Disease and Frontotemporal Dementia in Admixed Latin American Populations
Authors: Acosta-Uribe Juliana , Piña Escudero Stefanie D. , Cochran J. Nicholas , Taylor Jared W. , Castruita P. Alejandra , Jonson Caroline , Barinaga Erin A. , Roberts Kevin , Levine Alexandra R. , George Dawwod S. , ÁvilaFunes José Alberto , Behrens María I. , Bruno Martín A. , Brusco Luis I. , Custodio Nilton , Duran-Aniotz Claudia , Lopera Francisco , Matallana Diana L. , Slachevsky Andrea , Takada Leonel T. , Zapata-Restrepo Lina M. , Durón-Reyes Dafne E. , França Resende Elisa de Paula , Gelvez Nancy , Godoy Maria E. , Maito Marcelo A. , Javandel Shireen , Miller Bruce L. , Nalls Mike A. , Leonard Hampton , Vitale Dan , Bandres-Ciga Sara , Koretsky Mathew J. , Singleton Andrew B. , Pantazis Caroline B. , Valcour Victor , Ibañez Agustin , Kosik Kenneth S. , Yokoyama Jennifer S. ,   the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat)
Published: November 2024

Background

Latin America’s diverse genetic makeup, shaped by centuries of admixture, presents a unique opportunity to study Alzheimer’s disease dementia (AD) and frontotemporal dementia (FTD). Our aim is to identify genetic variations associated with AD and FTD within this population.

Methods

The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) recruited 2,162 participants with AD, FTD, and healthy controls from six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, and Peru). All participants underwent array, exome, and/or whole-genome sequencing. Population structure was analyzed using Principal Component Analysis and ADMIXTURE, projecting the ReDLat population onto the 1000 Genomes Project database. To identify genes associated with autosomal dominant, autosomal recessive, or X-linked forms of adult-onset dementia, we searched the Online Mendelian Inheritance in Man database and analyzed pedigree information. Variant interpretation followed guidelines from the American College of Medical Genetics and Genomics, and the Guerreiro algorithm was applied for thePSEN1andPSEN2genes.

Results

Global ancestry analysis of the ReDLat cohort revealed a predominant mix of American, African, and European ancestries. Uniquely, Brazil displayed an additional East Asian component accurately reflecting the historical admixture patterns from this region. We identified 17 pathogenic variants, a pathogenicC9orf72expansion, and 44 variants of uncertain significance. Among our cohort, 70 families exhibited autosomal dominant inheritance of neurodegenerative diseases, with 48 families affected by AD and 22 by FTD. In families with AD, We discovered a novel variant in thePSEN1gene, c.519G>T (p.Leu173Phe), along with other previously described variants seen in the region, such as c.356C>T (p.Thr119Ile). In families with FTD, the most commonly associated gene wasGRN, followed byMAPT. Notably, we identified a patient meeting criteria for FTD who carried a pathogenic variant inSOD1, c.388G>A (p.Phe21Leu), which had previously been reported in another FTD patient from the same geographical region.

Conclusions

This study provides the first snapshot of genetic contributors to AD and FTD in a multisite cohort across Latin America. It will be critical to evaluate the generalizability of genetic risk factors for AD and FTD across diverse ancestral backgrounds, considering distinct social determinants of health and accounting for modifiable risk factors that may influence disease risk and resilience across different cultures.