BackgroundDifferentiating tau-related dementias remains challenging, particularly during early disease stages when clinical symptoms overlap. Existing biomarkers mainly reflect downstream pathology and provide limited insight into disease-specific molecular processes.ObjectiveWe examined whether cerebrospinal fluid (CSF)-derived cell-free DNA (cfDNA) methylation could distinguish Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), and progressive supranuclear palsy (PSP).MethodsPromoter methylation of 20 genes associated with AD risk, neuroinflammation, cellular senescence, and glymphatic or lymphatic regulation was analyzed in CSF and matched plasma cfDNA from controls (n = 15), AD (n = 21), bvFTD (n = 14), and PSP (n = 17). cfDNA concentration and fragmentomic profiles were assessed. Diagnostic performance was evaluated using logistic regression and receiver operating characteristic (ROC) analysis. Findings were validated in an independent cohort.ResultsCSF cfDNA concentrations were increased in AD, whereas fragment size distributions were similar across diagnostic groups. Disease-associated methylation signatures were prominent in CSF but weak or absent in plasma. AD demonstrated widespread hypomethylation of inflammatory and senescence-associated genes together with hypermethylation of glymphatic and lymphatic regulators. bvFTD showed intermediate glial- and stress-related methylation changes, while PSP retained relatively preserved inflammatory and clearance-associated profiles. CSF methylation panels consistently outperformed plasma-derived markers for disease classification. ROC analyses demonstrated strong discrimination for AD, with AUC values reaching 0.84-0.85, while plasma-based markers showed limited diagnostic utility.ConclusionsCSF cfDNA methylation captures disease-specific epigenetic states linked to core pathogenic pathways in tau-related dementias. This approach may provide a biologically informative and clinically useful platform for molecular classification and diagnostic stratification.
