RESUMO
A number of genetic loci associate with early onset Alzheimer's disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and in vivo modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2ß confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to assess if genes associated with sporadic EOAD (sEOAD) are differentially methylated. Epi-profiles of DNA extracted from blood and cortex were compared using a pyrosequencing platform. We identified significant group-wide hypomethylation in AD blood when compared to controls for 7 CpGs located within the 3'UTR of RIN3 (CpG1 pâ=â0.019, CpG2 pâ=â0.018, CpG3 pâ=â0.012, CpG4 pâ=â0.009, CpG5 pâ=â0.002, CpG6 pâ=â0.018, and CpG7 pâ=â0.013, respectively; AD/Control nâ=â22/26; Male/Female nâ=â27/21). Observed effects were not gender specific. No group wide significant differences were found in the promoter methylation of PTK2ß, ABCA7, SIRT1, or MEF2C, genes known to associate with late onset AD. A rare and significant difference in methylation was observed for one CpG located upstream of the MEF2C promoter in one AD individual only (22% reduction in methylation, pâ=â2.0E-10; Control nâ=â26, AD nâ=â25, Male/Female nâ=â29/22). It is plausible aberrant methylation may mark sEOAD in blood and may manifest in some individuals as rare epi-variants for genes linked to sEOAD.