Histone Post-Translational Modifications at the Metabolism–Chromatin Interface: Reprogramming of Neuroinflammation in Alzheimer’s Disease

Increasing evidence implicates histone post-translational modifications in the persistence of neuroinflammation in Alzheimer’s disease (AD), yet how transient pathological insults are converted into sustained immune states remains unclear. In this Review, we examine histone PTMs as chromatin-based integrators of inflammatory, metabolic and proteotoxic signals that establish sustained transcriptional programmes. We summarize how histone marks regulate chromatin accessibility, enhancer activity and transcription factor recruitment, thereby shaping the magnitude, duration and reversibility of neuroimmune responses across microglia, astrocytes and neurons. We also discuss how amyloid-β, tau, metabolic dysfunction, senescence and innate immunity converge on chromatin remodelling, and consider emerging acylation pathways. Collectively, these observations support a model in which histone modifications sustain inflammatory programmes in a gene-locus- and cell-type-specific manner, encoding a form of pathological neuroimmune memory that may explain the persistence and heterogeneity of inflammation across disease stages. Understanding the establishment, maintenance and reversibility of these epigenetic states could identify therapeutic windows for targeted epigenetic interventions.