Sex-specific remodeling of the tRNA epitranscriptome in Alzheimer’s disease

tRNA modifications are critical regulators of RNA stability, decoding fidelity, and cellular stress adaptation, yet their contribution to human neurodegenerative disease remains poorly understood. Beyond their established functions in translational control, emerging evidence shows that RNA modifications influence neurogenesis, neurodevelopment, neuronal function, brain-cell differentiation, and cellular plasticity. Consequently, dysregulation of these molecular processes is increasingly recognized as a mechanistic contributor to neurodegenerative disorders. Alzheimer’s disease (AD), characterized by amyloid pathology, synaptic dysfunction, and progressive neuronal loss, has recently been linked to disturbances in RNA metabolism, suggesting that alterations in the epitranscriptome may represent an underexplored dimension of AD pathophysiology. Here, we systematically profiled the tRNA epitranscriptome across cellular and animal models of AD, as well as in human postmortem brain tissue from non-demented controls and AD patients, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This method enables highly sensitive quantification of RNA modifications, with limits of detection in the low femtomole range. Across our models, we identified a conserved yet sex-specific remodeling of the tRNA modification landscape in AD. Because therapeutic options and early diagnostic tools for AD remain limited, we leveraged these findings to develop a tRNA-centered RNA-modification score that integrates both nucleobase-specific modification patterns and neuropathological disease severity into a quantitative metric. Together, our findings identify the tRNA epitranscriptome as a unifying molecular sex-specific signature of AD, linking disease pathology and sex to impaired RNA metabolism. This line of research opens a new path toward establishing early biomarkers or diagnostic tools for AD.