DNA methylation patterns of LINE-1 and Alu for pre-symptomatic dementia in type 2 diabetes

The identification of early markers of dementia is important for higher-risk populations such as those with type 2 diabetes (T2D). Retrotransposons, including long interspersed nuclear element 1 (LINE-1) andAlu, comprise similar to 40% of the human genome. Although dysregulation of these retrotransposons can induce aberrant gene regulation and genomic instability, their role in the development of pre-symptomatic dementia (PSD) among T2D patients is unknown. Here, we examined locus-specific changes in LINE-1 andAlumethylation in PSD and the potential to offset these changes via supplementation with folate and vitamin B-12. We interrogated DNA methylation patterns corresponding to 22,352 probes for LINE-1 andAluelements using publicly-available Illumina Infinium 450K methylation datasets from i) an 18-month prospective study in 28 T2D patients (GSE62003) and ii) an intervention study in which 44 individuals were supplemented with folic acid (400 mu g/day) and vitamin B-12(500 mu g/day) over two years (GSE74548). We identified 714 differentially methylated positions (DMP) mapping to retrotransposons in T2D patients who developed PSD in comparison to those who did not (P-FDR< 0.05), comprised of 2.4% (228 probes) of all LINE-1 probes and 3.8% (486 probes) of allAluprobes. These loci were enriched in genes with functions related to Alzheimer's disease and cognitive decline, includingGNB5,GNG7andPKN3(p < 0.05). In older individuals supplemented with folate/vitamin B-12, 85 (11.9%) PSD retrotransposon loci showed significant changes in methylation (p < 0.05): participants with theMTHFRCC genotype predominantly showed hypermethylation at these loci, while hypomethylation was observed more frequently in those with the TT genotype. In T2D patients, LINE-1 andAluelements are differentially methylated in PSD in a locus-specific manner and may offer clinical utility in monitoring risk of dementia. Further work is required to examine the potential for dietary supplementation in lowering the risk of PSD.