Epigenetic Aging in Alzheimer’s Disease: Molecular Mechanisms Linking Chromatin Remodeling, Neuroinflammation, and Progressive Neurodegeneration
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder
and represents a major global health burden associated with aging
populations. Although amyloid-β deposition and tau pathology remain
classical hallmarks of AD, increasing evidence suggests that epigenetic
aging critically contributes to disease initiation and progression through
dynamic alterations in chromatin organization, DNA methylation, histone
modifications, and non-coding RNA regulation. Epigenetic drift during
aging promotes transcriptional instability, neuroinflammatory activation,
mitochondrial dysfunction, synaptic impairment, and neuronal
vulnerability, thereby accelerating neurodegenerative processes. Emerging
studies further demonstrate that chromatin remodeling complexes and age-
associated epigenomic alterations influence microglial activation, blood-
brain barrier integrity, and cellular senescence within the Alzheimer’s brain
microenvironment. Advances in multi-omics technologies and epigenetic
profiling have substantially improved the understanding of molecular
interactions linking aging biology with neurodegeneration. Furthermore,
the reversibility of epigenetic modifications has generated significant
interest in epigenetic-targeted therapeutic interventions, including histone
deacetylase inhibitors, DNA methylation modulators, senolytic
approaches, and precision medicine strategies. This review discusses the
mechanistic interplay between epigenetic aging and Alzheimer’s disease,
emphasizing chromatin remodeling, neuroinflammation, and emerging
translational opportunities for therapeutic intervention.
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