Early epigenetic changes of Alzheimer's disease in the human hippocampus.

ABSTRACT

The discovery of new biomarkers would be very valuable to improve the detection of early Alzheimer's disease (AD). DNA methylation marks may serve as epigenetic biomarkers of early AD. Here we identified epigenetic marks that are present in the human hippocampus from the earliest stages of AD. A previous methylome dataset of the human AD hippocampus was used to select a set of eight differentially methylated positions (DMPs) since early AD stages. Next, bisulphite pyrosequencing was performed in an expanded homogeneous cohort of 18 pure controls and 35 hippocampal samples with neuropathological changes of pure AD. Correlation between DNA methylation levels in DMPs and phospho-tau protein burden assessed by immunohistochemistry in the hippocampus was also determined. We found four DMPs showing higher levels of DNA methylation at early AD stages compared to controls, involving ELOVL2, GIT1/TP53I13 and the histone gene locus at chromosome 6. DNA methylation levels assessed by bisulphite pyrosequencing correlated with phospho-tau protein burden for ELOVL2 and HIST1H3E/HIST1H3 F genes. In this discovery study, a set of four epigenetic marks of early AD stages have been identified in the human hippocampus. It would be worth studying in-depth the specific pathways related to these epigenetic marks. These early alterations in DNA methylation in the AD hippocampus could be regarded as candidate biomarkers to be explored in future translational studies. ABBREVIATIONS AD Alzheimer's disease; DMPs Differentially methylated positions; CSF Cerebrospinal fluid; ßA42 ß-amyloid 42; PET positron emission tomography; 5mC 5-methyl cytosine; CpG cytosine-guanine dinucleotides; ANK1 ankyrin-1; BIN1 amphiphysin II; p-tau hyperphosphorylated tau; CERAD Consortium to Establish A Registry for Alzheimer's Disease; SD standard deviation; ANOVA one-way analysis of variance; VLCFAs very long-chain fatty acids; DHA docosahexaenoic acid; mTOR mechanistic target of rapamycin.