Genome-Wide DNA Methylation in Early-Onset-Dementia Patients Brain Tissue and Lymphoblastoid Cell Lines

[EN] Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer's disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted p-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue. This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects PI17/00670 to A.A., PI20/00448 to R.S.-V. and FI18/00121 to O.R.-C., and co-funded by the European Union. Departament de Salut de la Generalitat de Catalunya (PERIS 2016 2020, SLT002/16/00329 and PERIS 2019 2021, SLT008/18/00061 ); Departament de Recerca i Universitats de la Generalitat de Catalunya, AGAUR group 2021-SGR-01126. The Article Processing Charge will be funded by University of Barcelona. Ramos-Campoy, O.; Comas-Albertí, A.; Hervás-Marín, D.; Borrego-Ecija, S.; Bosch, B.; Sandoval, J.; Fort-Aznar, L... (2024). Genome-Wide DNA Methylation in Early-Onset-Dementia Patients Brain Tissue and Lymphoblastoid Cell Lines. International Journal of Molecular Sciences. 25(10). https://doi.org/10.3390/ijms25105445