Narrative review: translating DNA methylation in dementia

DNA methylation (DNAm) is a promising biomarker but remains underutilized in routine clinical practice. As an early molecular event, DNAm often occurs before changes in gene expression or protein production, making it valuable for early disease detection. In diabetes, a known risk factor for dementia, changes in DNAm can occur 80-90 days before detectable alterations in protein expression. Furthermore, emerging evidence indicates that DNAm patterns may be present as early as eight years before the onset of dementia. However, DNAm analysis requires specific sample types because methylation is tissue-dependent, and invasive biopsies are often impractical. Cell-free DNA (cfDNA) offers a feasible alternative, as it can reflect brain pathology through analysis of DNAm patterns in accessible body fluids. This review explores the mechanisms of dementia-related cfDNA release and detection in cerebrospinal fluid, blood, tears, saliva, and urine, and highlights the broader applications of DNAm beyond early diagnosis. Future research should carefully address tissue specificity in sample selection and focus on developing simplified DNAm assays to facilitate widespread clinical implementation.