Epigenetic Remodeling in Alzheimer’s Disease: Mechanistic Insights and Therapeutic Opportunities

Abstract

Background: Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disorder and a leading cause of dementia, involving the gradual loss of cognitive function, memory, and neurons. While the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), caused by hyperphosphorylation of the protein tau, continue to be recognized as hallmarks of AD pathology, emerging evidence suggests that epigenetic dysregulation plays a crucial role in disease initiation and progression.

Purpose: The current review highlights the role of epigenetic remodeling in AD pathogenesis, emerging biomarkers associated with epigenetics, therapeutic strategies, and translational challenges.

Methods: This narrative review was conducted through a structured literature search of PubMed, Scopus, and Web of Science databases following the PRISMA framework. Relevant studies on epigenetic mechanisms, biomarkers, and therapeutic strategies in AD were screened and critically reviewed.

Results: Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation, affect gene expression without changing the underlying DNA sequence and serve as a critical interface between genetic susceptibility, aging, and environment. Aberrant DNA methylation, changes in histone acetylation, methylation, phosphorylation, and ubiquitination, along with the dysregulation of microRNAs and long noncoding RNA, all play a role in amyloidosis, tauopathy, inflammation, oxidative damage, synaptic dysfunction, and neuronal loss. Additionally, several biomarkers related to epigenetics such as ANK1 methylation, miR-29a/b, miR-107, miR-132, miR-146a, and BACE1-AS have been discovered as potential disease biomarkers. Epigenetic therapeutics involving histone deacetylase inhibitors, DNA methyltransferase regulators, sirtuin-targeting agents, and RNA-based therapeutics have demonstrated neuroprotective effects in preclinical models of AD. Nevertheless, there are certain obstacles that limit their utility, such as insufficient blood-brain barrier (BBB) permeability, off-target effects, and poor clinical translation.

Conclusion: Advancing our understanding of the epigenetic landscape of AD may facilitate the development of precision diagnostics and disease-modifying therapies.

  • Page Number : 74-86
  • Published Date : 2026-09-18
  • Keywords
    Alzheimer’s disease, Biomarkers, Epigenetics, Histone modifications, Therapeutics
  • DOI Number
    10.15415/jptrm.2026.141003
  • Authors
    Amanpreet Kaur, Geeta Aggarwal and Vetriselvan Subramaniyam

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