Pathogenic Protein Post-Translational Modifications in Alzheimer's Disease: Mechanisms and Therapeutic Strategies

Alzheimer's Disease (AD) pathology involves much more than just Amyloid- Beta (Aβ) and tau (Tau) deposition. A broad network of Post-Translational Modifications (PTMs) drives pathogenic protein conformations that accelerate neuroinflammation, synaptic dysfunction, aggregation, and trans-neuronal spread. Characterising PTM-dependent biochemical signatures allows earlier diagnosis and supports the development of molecularly targeted therapies.

A comprehensive review was performed with clinical-trial registries, high-confidence proteomic repositories, and major bibliographic databases from 2000 to 2024, in line with PRISMA guidelines. Bioinformatic tools, curated PTM databases, protein-interaction networks, and computational structure-prediction platforms were utilized to analyse PTM interactions, pathway convergence, and structural impacts.

These include multiple PTMs such as phosphorylation, acetylation, truncation, glycation, oxidation, nitration, ubiquitination, SUMO conjugation, and O-GlcNAc modification that reshape Tau and Aβ solubility, trafficking, aggregation propensity, and clearance efficiency. Human brain proteomics has revealed stage-specific PTM signatures, providing evidence for a combinatorial "PTM code" that dictates disease progression. These PTM-defined proteoforms have directly informed biomarker development, e.g., plasma/Cerebrospinal Fluid (CSF) phosphorylated tau (p-tau) 217/231, and have improved therapeutic precision, including antibodies targeting pyroglutamatemodified Aβ. Therapeutic innovation is targeting kinases, phosphatases, acetylation machinery, OGlcNAc cycling enzymes, oxidative stress pathways, and proteostasis networks alongside RNAbased tau-lowering agents, PTM-guided immunotherapies, and rational combination strategies.

PTMs are a central, actionable dimension linking molecular pathology, biomarker specificity, and therapeutic response in AD. The integration of PTM signatures into discovery pipelines and clinical-trial frameworks may help to advance precision diagnostics and yield more effective, disease-modifying interventions.