Epigenetic Dysregulation in Neurodegenerative Disease: Implications for Neuropathology and Therapy

Abstract

Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by progressive neuronal dysfunction, yet their underlying mechanisms remain incompletely understood. Emerging evidence implicates epigenetic dysregulation as a central contributor to the pathogenesis of these disorders. A thematic literature review was conducted across major databases using targeted search terms related to epigenetics and neurodegeneration. Studies were selected based on relevance, methodological quality, and contribution to mechanistic understanding, in accordance with Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. Across AD, PD, and HD, distinct yet overlapping patterns of epigenetic alterations were identified. In AD, dysregulated DNA methylation and histone acetylation affect genes linked to amyloid and tau pathology. In PD, hypomethylation of SNCA and altered histone acetylation contribute to α-synuclein overexpression and neuronal loss. In HD, mutant huntingtin protein disrupts chromatin remodeling by sequestering histone acetyltransferases and altering microRNA expression. These changes disrupt neuronal identity, synaptic function, and inflammatory responses, often forming feedback loops that exacerbate disease progression. Epigenetic mechanisms play a pivotal role in neurodegeneration by mediating gene-environment interactions and perpetuating neuropathological changes. Their reversible nature presents opportunities for therapeutic intervention, though challenges related to specificity, delivery, and timing remain. Continued research into epigenetic biomarkers and precision-targeted epigenetic therapies holds promise for advancing early diagnosis and disease modification in NDDs.