迫切需要确定用于阿尔茨海默病（AD）诊断的新型非侵入性生物标志物。磷酸化 tau (pTau) 物种的血液测量的最新进展令人鼓舞，但仍不足以满足临床需求。表观遗传学已被证明有助于更好地了解 AD 发病机制。表观遗传生物标志物已成功应用于肿瘤学等其他医学学科。该研究的目的是探索基于血液的 DNA 甲基化标记物组作为非侵入性工具与年龄匹配的对照相比的诊断准确性，以识别迟发性阿尔茨海默病患者。进行了病例对照研究。根据 NIA-AA 指南（2011 年）和神经科招募的年龄和性别匹配对照，通过亚硫酸氢盐焦磷酸测序法测量了 46 个 CpG 位点（综合文献检索后选择的 21 个基因）的血液 DNA 甲基化水平。西班牙纳瓦拉大学医院科室，通过便利抽样选出。通过 Simoa 技术测定血浆 pTau181 水平。进行多变量逻辑回归分析以探索区分 AD 患者与对照组的最佳模型。此外，我们按性别进行了分层分析。最终研究队列由 80 名 AD 患者（年龄中位数 (IQR) = 79 (11)；58.8% 女性）和 100 名认知健康对照者（年龄 77 (10)；58%女性）。包含 NXN、TREML2、ABCA7 和 HOXA3 基因和血浆 pTau181 的 DNA 甲基化水平的一组显着改善（AUC [95% CI]=0.93[0.89-0.97]）基于单一 pTau181 的模型的诊断性能（根据年龄进行调整），性别和 APOE ɛ4 基因型。该小组的敏感性和特异性分别为 83.30% 和 90.00%。经过性别分层分析后，HOXA3 DNA 甲基化水平显示与 AD 一致相关。这些结果凸显了基于血液的 DNA 甲基化生物标志物对于 AD 无创诊断的潜在转化价值。纳瓦拉大学医院研究伦理委员会 (PI17/ 02218).版权所有 © 2023 作者。由 Wolters Kluwer Health, Inc. 代表美国神经病学学会出版。

There is an urgent need to identify novel non-invasive biomarkers for Alzheimer's disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of the study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a non-invasive tool to identify late-onset Alzheimer patients, compared to age-matched controls.A case-control study was performed. Blood DNA methylation levels at 46 CpG sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with "probable AD dementia" following NIA-AA guidelines (2011) and age- and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate AD patients from controls. Furthermore, we carried out a stratified analysis by sex.Final study cohort consisted of 80 AD patients (age-median (IQR) = 79 (11); 58.8% female) and 100 cognitively healthy controls (age 77 (10); 58% female). A panel including DNA methylation levels at NXN, TREML2, ABCA7 and HOXA3 genes and plasma pTau181 significantly improved (AUC [95% CI]=0.93[0.89-0.97]) the diagnostic performance of a single pTau181-based model, adjusted for age, sex and APOE ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, HOXA3 DNA methylation levels showed consistently associated to AD.These results highlight the potential translational value of blood-based DNA methylation biomarkers for non-invasive diagnosis of AD.Research Ethics Committee of the University Hospital of Navarre (PI17/02218).Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.