Developing Topics

Alzheimers Dement. 2025 Dec;21 Suppl 7:e108949. doi: 10.1002/alz70861_108949.

ABSTRACT

BACKGROUND: Genetic studies for Alzheimer's disease and related dementias are underrepresented in Latin America. The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) cohort recruits from ten centers in six countries across Latin America, providing an opportunity to address this shortcoming.

METHOD: 2,736 participants with available genetic material were assessed via Illumina genome sequencing. Genetic ancestry was determined via the package GenoTools and data were analyzed separately by genetic ancestry group. The largest genetic ancestry group was admixed American (AMR) with 2,147 individuals. Of these 2,147 individuals, 65 were excluded in quality control steps leaving 981 controls, 771 AD, 298 FTD, and 32 with other or indeterminate phenotypes. GWAS was conducted using GEMMA which adjusts for admixture and familial relationships using a kinship matrix. Burden analysis was also conducted with adjustment via a kinship matrix.

RESULT: In the AD GWAS, the only genome-wide significant (p < 5x10^-8) hit in preliminary analysis was the APOE locus, with rs429358 (which tags the APOE ε4 allele) as the lead snv with p = 8x10^-42. 103 independent loci (defined by separation by at least 1 MB) exhibited suggestive significance (p < 1x10^-5), with 7 of these beyond the APOE locus exhibiting replication with at least p < 0.05 and consistent direction betas for the effect allele in Bellenguez, et al. 2022 summary statistics. These loci included rs113181288 on chromosome 1 Between ELF3 and ENSG00000294430, rs4971744 on chromosome 2 (NRXN1-DT intronic), rs76343365 on chromosome 4 between ENSG00000289869 and ENSG00000250945, rs7442695 on chromosome 5 (ENSG00000294529 intronic), rs62437151 on chromosome 6 (ENSG00000223786 intronic), rs117134121 on chromosome 10 (ADARB2 Intronic), and rs2278745 on chromosome 10 (HK1 Intronic). GWAS for FTD and burden analyses for AD and FTD are underway.

CONCLUSION: Expansion of recruitment efforts for genetic studies in ADRD has great potential to nominate new hits for further study. This analysis is an important step forward for representation of Latin Americans in genetic association studies for ADRD.

PMID:41434578 | DOI:10.1002/alz70861_108949