<p>Alzheimer’s disease (AD) is a progressive neurodegenerative condition marked by the accumulation of amyloid-β (Aβ), tau hyperphosphorylation, synaptic dysfunction, and ongoing neuroinflammation. Recent findings emphasize the role of post-translational modifications (PTMs) such as phosphorylation, ubiquitination, SUMOylation, methylation, acetylation, palmitoylation, prenylation, and O-GlcNAcylation as crucial molecular switches that influence protein stability, localization, aggregation, and signaling. Disrupted PTMs interfere with APP processing, increase Aβ production, encourage tau misfolding and the formation of neurofibrillary tangles, hinder proteostasis networks, and intensify inflammatory pathways. This review compiles mechanistic insights into how abnormal PTMs contribute to AD pathogenesis and assesses therapeutic strategies that target PTM-regulated pathways. Notable agents like BACE1 inhibitors, HDAC6 modulators, GSK-3β inhibitors, O-GlcNAcase inhibitors, PDE3 modulators, and farnesyltransferase inhibitors show promising preclinical outcomes, including decreased Aβ and tau pathology, enhanced axonal transport, and cognitive improvement. Nevertheless, the clinical application is still constrained by inadequate CNS penetration, off-target toxicity, compensatory pathway activation, and the limited capacity of existing models to mimic human PTM dynamics. Advancing PTM-targeted therapies will require brain-penetrant, isoform-selective compounds supported by multi-omics biomarkers and precision medicine approaches that stratify patients by PTM profiles. Combining PTM modulation with anti-amyloid, anti-tau, or immunomodulatory strategies may enhance disease-modifying potential. PTMs therefore remain a promising yet underutilized therapeutic frontier in AD.</p> Graphical abstract <p></p>