Pishva Ehsan, Bertram Lars, Lunnon Katie
Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, the Netherlands.
Alzheimers Dement. 2025 Sep;21(9):e70646. doi: 10.1002/alz.70646.
Epigenetic mechanisms act as mediators of genetic and environmental influences. In Alzheimer's disease, blood-based DNA methylation signatures are increasingly being explored as minimally invasive peripheral biomarkers. We previously reported associations between blood DNA methylation in the CHI3L1 gene (encoding YKL-40) and cerebrospinal fluid (CSF) levels of YKL-40, a marker of neuroinflammation. These findings have now been replicated in an independent study (Kaleck et al. 2025), reinforcing their robustness and biological relevance. We also reported associations between DNA methylation and CSF neurofilament light chain levels, a marker of axonal damage, which were not independently replicated in the analyses by Kaleck et al. Several factors may have contributed to this inconsistency in results, which we discuss in detail as they are relevant to future DNA methylation-based studies in the field. Together, these findings highlight both the potential and the complexity of identifying consistent blood-based epigenomic signatures for neurodegenerative processes. They also underscore the importance of harmonizing methodologies across studies to improve reproducibility and, eventually, to yield meaningful biomarkers allowing an early detection of this devastating disease.
表观遗传机制充当基因和环境影响的介质。在阿尔茨海默病中，基于血液的DNA甲基化特征正越来越多地被探索为微创外周生物标志物。我们之前报道了CHI3L1基因（编码YKL-40）中的血液DNA甲基化与YKL-40的脑脊液（CSF）水平之间的关联，YKL-40是一种神经炎症标志物。这些发现现已在一项独立研究（Kaleck等人，2025年）中得到重复，增强了它们的稳健性和生物学相关性。我们还报道了DNA甲基化与CSF神经丝轻链水平之间的关联，神经丝轻链是轴突损伤的标志物，但在Kaleck等人的分析中并未独立重复出来。几个因素可能导致了结果的这种不一致性，我们将详细讨论这些因素，因为它们与该领域未来基于DNA甲基化的研究相关。总之，这些发现凸显了为神经退行性过程识别一致的基于血液的表观基因组特征的潜力和复杂性。它们还强调了在各项研究中统一方法以提高可重复性的重要性，并最终产生有意义的生物标志物，以便能够早期检测这种毁灭性疾病。
