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[Preprint]. 2025 May 6:rs.3.rs-5462510.
doi: 10.21203/rs.3.rs-5462510/v1.

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

Juliana Acosta-Uribe  1 , Stefanie D Piña Escudero  2 , J Nicholas Cochran  3 , Jared W Taylor  3 , P Alejandra Castruita  4 , Caroline Jonson  4 , Erin A Barinaga  3 , Kevin Roberts  3 , Alexandra R Levine  4 , Dawwod S George  1 , José Alberto Avila-Funes  5 , María I Behrens  6 , Martin A Bruno  7 , Luis I Brusco  8 , Nilton Custodio  9 , Claudia Duran-Aniotz  10 , Francisco Lopera  11 , Diana L Matallana  12 , Andrea Slachevsky  6 , Leonel T Takada  13 , Lina M Zapata-Restrepo  14 , Dafne E Durón-Reyes  5 , Elisa de Paula França Resende  15 , Luisa F Gómez  16 , Nancy Gelvez  16 , M Beatriz Bistue  7 , Maria E Godoy  10 , Marcelo A Maito  10 , Shireen Javandel  2 , Bruce L Miller  2 , Mike A Nalls  17 , Hampton Leonard  17 , Dan Vitale  17 , Sara Bandres-Ciga  18 , Mathew J Koretsky  17 , Andrew B Singleton  18 , Caroline B Pantazis  18 , Victor Valcour  2 , Agustin Ibañez  10 , Kenneth S Kosik  4 , Jennifer S Yokoyama  2 ; Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat)
Affiliations

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

Juliana Acosta-Uribe et al. Res Sq. .

Abstract

Latin America's diverse genetic landscape provides a unique opportunity to study Alzheimer's disease (AD) and frontotemporal dementia (FTD). The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) recruited 2,162 participants with AD, FTD, or as healthy controls from six countries: Argentina, Brazil, Chile, Colombia, Mexico, and Peru. Participants underwent genomic sequencing and population structure analyses were conducted using Principal Component Analysis and ADMIXTURE. The study revealed a predominant mix of American, African, and European ancestries, with an additional East Asian component in Brazil. Variant curation identified 17 pathogenic variants, pathogenic C9orf72 expansion, and 44 variants of uncertain significance. Seventy families showed autosomal dominant inheritance, with 48 affected by AD and 22 by FTD. This represents the first large-scale genetic study of AD and FTD in Latin America, highlighting the need to consider diverse ancestries, social determinants of health, and cultural factors when assessing genetic risk for neurodegenerative diseases.

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Conflict of interest statement

Declarations Competing interests M.A.N. owns stock from Character Bio Inc and Neuron23 Inc. K.S.K. and J.S.Y. are members of the scientific advisory board of the Epstein Family Alzheimer’s Research Collaboration. K.S.K. is a member of the board of directors of the Tau Consortium and consults with Expansion Therapeutics and ADRx Pharma. J.S.Y. is Editor-in-Chief for npj Dementia. J.S.Y. was not involved in the journal’s review of, or decisions related to, this manuscript.

Figures

Figure 1
Figure 1. Assembly of ReDLat genomic dataset.
WES: whole exome sequencing. WGS: whole genome sequencing. SNP: single nucleotide polymorphism
Figure 2
Figure 2. Principal component analysis of the ReDLat dataset and individuals from the 1000 Genome project (1000GP).
The 1000 Genomes project includes African (AFR), European (EUR), South Asian (SAS), East Asian (EAS) and Admixed American (AMR) individuals. ReDLat sub-cohorts include individuals from Argentina (ARG), Brazil (BRA), Chile (CHI), Colombia (COL), Mexico (MEX) and Peru (PER). PC: Principal component. a) PC1 vs. PC2. Genomes from ReDLat are colored by sub-cohort, while all 1000GP genomes are shown in a single color. b) PC1 vs. PC3. Genomes from ReDLat are colored by sub-cohort, while all 1000GP genomes are shown in a single color. c) PC2 vs. PC3. Genomes from ReDLat are colored by sub-cohort, while all 1000GP genomes are shown in a single color. d) PC1 vs. PC2. Genomes from 1000GP are colored by sub-cohort, while all ReDLat genomes are shown in a single color. e) PC1 vs. PC3. Genomes from 1000GP are colored by sub-cohort, while all ReDLat genomes are shown in a single color. f) PC2 vs. PC3. Genomes from 1000GP are colored by sub-cohort, while all ReDLat genomes are shown in a single color. g) PC1 vs. PC2 of ReDLat and 1000GP genomes. h) PC1 vs. PC3 of ReDLat and 1000GP genomes. i) PC1 vs. PC2 of ReDLat and 1000GP genomes.
Figure 3
Figure 3. Global ancestry proportions of the ReDLat cohort represented by ADMIXTURE Q. values assuming 5 ancestral populations (K)
The 1000 Genomes project includes African (AFR): GWD: Gambian in Western Divisions in the Gambia, LWK: Luhya in Webuye, MSL: Mende in Sierra Leone, YRI: Yoruba in Ibadan, Nigeria, ACB: African Caribbean in Barbados, ASW: African Ancestry in Southwest US. European (EUR): CEU: Utah Residents (CEPH) with Northern and Western European Ancestry, FIN: Finnish in Finland, GBR: British in England and Scotland, IBS: Iberian Population in Spain, TSI: Tuscany in Italia. South Asian (SAS): BEB: Bengali in Bangladesh, GHI: Gujarati Indians in Houston, ITU: Indian Telugu in the U.K., PJL: Punjabi in Lahore, STU: Sri Lankan Tamil in the UK. East Asian (EAS): CDX: Chinese Dai in Xishuangbanna, China, CHB: Han Chinese in Beijing, CHS: Han Chinese South, JPT: Japanese, Kyushu, KHV: Kinh Vietnamese. Admixed American (AMR): CLM: Colombian from Medellin, PUR: Puerto Rican from Puerto Rico. ReDLat subcohorts: ARG: Argentina, BRA: Brazil, CHI: Chile, COL: Colombia, MEX: Mexico, PER: Peru
Figure 4
Figure 4. Cosegregation analysis of APOE ε4and neurodegeneration in families with multiple affected individuals
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