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; βA42: β-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.

中文翻译：

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人类海马体中阿尔茨海默氏病的早期表观遗传变化。

新生物标志物的发现对于改善早期阿尔茨海默氏病（AD）的检测将非常有价值。DNA甲基化标记可以作为早期AD的表观遗传标记。在这里，我们确定了从AD最早出现在人类海马中的表观遗传标记。自AD早期以来，就使用了人类AD海马的先前甲基化组数据集来选择一组八个差异甲基化位置（DMP）。接下来，在18个纯对照和35个海马样品的扩展同质队列中进行亚硫酸氢焦磷酸测序，并进行纯AD的神经病理学改变。还确定了海马中DMP中DNA甲基化水平与通过免疫组织化学评估的磷酸化tau蛋白负荷之间的相关性。ELOVL2，GIT1 / TP53I13和组蛋白基因位于6号染色体。通过亚硫酸氢盐焦磷酸测序评估的DNA甲基化水平与ELOVL2和HIST1H3E / HIST1H3 F基因的磷酸化tau蛋白负荷相关。在这项发现研究中，已在人类海马体中发现了AD早期的四个表观遗传标记。值得深入研究与这些表观遗传标记有关的特定途径。这些在AD海马中DNA甲基化的早期改变可以被视为候选的生物标志物，将在未来的翻译研究中进行探索。

缩略语

AD：阿尔茨海默氏病；DMP：差异甲基化位置；脑脊液：脑脊液；βA42：β-淀粉样蛋白42；PET：正电子发射断层扫描；5mC：5-甲基胞嘧啶；CpG：胞嘧啶-鸟嘌呤二核苷酸；ANK1：锚蛋白1；BIN1：两栖生物素II；p-tau：磷酸化tau；CERAD：财团将建立阿尔茨海默氏病注册系统；SD：标准偏差；方差分析：方差的单向分析；VLCFA：超长链脂肪酸；DHA：二十二碳六烯酸；mTOR：雷帕霉素的机械靶标。