Abstract
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.