Methylomic signatures of tau and amyloid-beta in transgenic mouse models of Alzheimer's disease neuropathology

Alzheimer's disease (AD) is characterized by progressive neurodegeneration driven by tau and amyloid-β (Aβ) pathology, although the underlying molecular mechanisms remain incompletely understood. Emerging evidence implicates a role for epigenetic modifications, particularly altered DNA methylation (DNAm), in AD pathogenesis. However, few studies have comprehensively investigated DNAm in experimental models. Here, we profile DNAm dynamics in two widely used transgenic mouse models of tau (rTg4510) and Aβ (J20) neuropathology, focusing on variation in the entorhinal cortex and hippocampus. Using reduced representation bisulfite sequencing (RRBS) and methylation arrays across multiple disease stages, we identified widespread DNAm alterations associated with genotype and neuropathological burden in both models. In rTg4510 mice, tau accumulation was linked to extensive DNAm remodeling at genes involved in neuronal plasticity, apoptosis, lipid metabolism, including Dcaf5, Creb3l4, and As3mt. J20 mice exhibited more modest changes annotated to immune-related genes, notably at Grk2, Ncam2, and Prmt8. Of note, tau-associated DNAm changes were more consistent across brain areas than those associated with Aβ pathology. Comparison with DNAm data from human studies revealed that a subset of DNAm sites mirrored those observed in the human AD cortex, including hypermethylation at Ank1 and Prdm16 in rTg4510 mice. These findings provide evidence for early, pathology-associated epigenetic alterations in AD, highlight both shared and distinct DNAm signatures of tau and Aβ, and offer insight into molecular mechanisms that may precede overt neurodegeneration. Our work underscores the utility of epigenomic profiling in transgenic models and provides a foundation for identifying novel targets for early intervention in AD.