Genetic Contributions to Alzheimer's Disease and Frontotemporal Dementia in Admixed Latin American Populations

Abstract

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 the PSEN1 and PSEN2 genes.

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 pathogenic C9orf72 expansion, 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 the PSEN1 gene, 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 was GRN, followed by MAPT. Notably, we identified a patient meeting criteria for FTD who carried a pathogenic variant in SOD1, 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.

Keywords: Admixture; Alzheimer’s disease; Autosomal dominant dementia; Frontotemporal dementia; Latin America; Neurodegeneration.

Figure 1.. Consort Diagram of the ReDLat Cohort

SNP: Single Nucleotide Polymorphism, WES: Whole exome sequencing, WGS: Whole genome sequencing

Figure 2.. Principal component analysis (PCA) of the ReDLat cohort.

A-B-C: ReDLat sub-cohort distribution compared to the 1000GP. D-E-F: 1000GP sub-cohort distribution compared to ReDLat. G-H-I: ReDLat compared to the 1000GP. A-D-G: PC1 vs. PC2. B-E-H: PC1 vs. PC3. C-F-G: PC2 vs. PC3 1000GP: Reference dataset from the 1000 Genomes project; AFR: African, AMR: American admixed, EAS: Eastern Asia, EUR: Europe, SAS: South Asian. ReDLat subcohorts include ARG: Argentina, BRA: Brazil, CHI: Chile, COL: Colombia, MEX: Mexico, PER: Peru

Figure 3.. Global ancestry of ReDLat cohorts

Reference panel from the 1000 Genomes project; AFR: African, AMR: American admixed, EAS: Eastern Asia, EUR: Europe, SAS: South Asian. (see supplementary figure2)

Figure 4.

Segregation of neurodegeneration in the ReDLat recruited cohort