BACKGROUND Trisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer's disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals. MATERIALS AND METHODS A genome-wide DNA methylation study was performed using Illumina Infinium® MethylationEPIC BeadChips on whole blood DNA of 3 male T21 patients with low IQ, 8 T21 patients with high IQ (4 males and 4 females), and 21 age- and sex-matched control samples (12 males and 9 females) in order to determine whether DNA methylation alterations could help explain variation in cognitive impairment between individuals with T21. In view of the increased risk of developing AD in T21 individuals, we additionally investigated the T21-associated sites in published blood DNA methylation data from the AgeCoDe cohort (German study on Ageing, Cognition, and Dementia). AgeCoDe represents a prospective longitudinal study including non-demented individuals at baseline of which a part develops AD dementia at follow-up. RESULTS Two thousand seven hundred sixteen differentially methylated sites and regions discriminating T21 and healthy individuals were identified. In the T21 high and low IQ comparison, a single CpG located in the promoter of PELI1 was differentially methylated after multiple testing adjustment. For the same contrast, 69 differentially methylated regions were identified. Performing a targeted association analysis for the significant T21-associated CpG sites in the AgeCoDe cohort, we found that 9 showed significant methylation differences related to AD dementia, including one in the ADAM10 gene. This gene has previously been shown to play a role in the prevention of amyloid plaque formation in the brain. CONCLUSION The differentially methylated regions may help understand the interaction between methylation alterations and cognitive function. In addition, ADAM10 might be a valuable blood-based biomarker for at least the early detection of AD.

中文翻译：

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21三体组的甲基化分析可识别与认知和阿尔茨海默氏病相关的调节异常。

背景技术21三体性疾病（T21）与轻度至重度智力障碍相关，平均智力商数约为50。此外，T21患者在生命早期发展为阿尔茨海默氏病（AD）的风险很高，其特征在于存在淀粉样蛋白和神经原纤维缠结的老年斑，导致神经元丢失和认知能力下降。我们假定表观遗传因素有助于观察到的智力障碍的变异性，以及在T21个体中所见的神经退行性变的水平。材料与方法使用IlluminaInfinium®MethylationEPIC BeadChips对3例智商低的男性T21患者，8例智商高的T21患者（4例男性和4例女性）的全血DNA进行了全基因组DNA甲基化研究，和21个年龄和性别匹配的对照样本（12例男性和9例女性），以确定DNA甲基化改变是否可以帮助解释T21患者之间认知障碍的变化。鉴于在T21个体中发生AD的风险增加，我们还从AgeCoDe队列（德国关于衰老，认知和痴呆的研究）发表的血液DNA甲基化数据中进一步研究了与T21相关的位点。AgeCoDe代表一项前瞻性纵向研究，包括基线时未痴呆的个体，其一部分在随访时发展为AD痴呆。结果鉴定了区分T21和健康个体的2 761个差异甲基化位点和区域。在T21高智商和低智商的比较中，经过多次测试调整后，位于PELI1启动子中的单个CpG被差异甲基化。出于相同的对比，确定了69个差异甲基化区域。对AgeCoDe队列中重要的与T21相关的CpG位点进行了针对性的关联分析，我们发现9个患者显示出与AD痴呆症相关的重要甲基化差异，包括ADAM10基因中的一个。先前已证明该基因在预防脑内淀粉样斑块形成中起作用。结论差异甲基化区域可能有助于理解甲基化改变与认知功能之间的相互作用。此外，ADAM10至少对于早期检测AD可能是有价值的基于血液的生物标记。鉴定出69个差异甲基化区域。对AgeCoDe队列中重要的与T21相关的CpG位点进行有针对性的关联分析，我们发现9个患者显示出与AD痴呆症相关的重要甲基化差异，包括ADAM10基因中的一个。先前已证明该基因在预防脑内淀粉样斑块形成中起作用。结论差异甲基化区域可能有助于理解甲基化改变与认知功能之间的相互作用。此外，ADAM10至少对于早期检测AD可能是有价值的基于血液的生物标记。鉴定出69个差异甲基化区域。对AgeCoDe队列中重要的与T21相关的CpG位点进行有针对性的关联分析，我们发现9个患者显示出与AD痴呆症相关的重要甲基化差异，包括ADAM10基因中的一个。先前已证明该基因在预防脑内淀粉样斑块形成中起作用。结论差异甲基化区域可能有助于理解甲基化改变与认知功能之间的相互作用。此外，ADAM10至少对于早期检测AD可能是有价值的基于血液的生物标记。包括ADAM10基因中的一个。先前已证明该基因在预防脑内淀粉样斑块形成中起作用。结论差异甲基化区域可能有助于理解甲基化改变与认知功能之间的相互作用。此外，ADAM10至少对于早期检测AD可能是有价值的基于血液的生物标记。包括ADAM10基因中的一个。先前已证明该基因在预防脑内淀粉样斑块形成中起作用。结论差异甲基化区域可能有助于理解甲基化改变与认知功能之间的相互作用。此外，ADAM10至少在早期发现AD时可能是有价值的基于血液的生物标记。