tRNA-Derived Small RNAs in Alzheimer’s Disease: Interpreting Fragmented Observations Through a Stress–Translation Framework

Alzheimer’s disease (AD) is traditionally explained by amyloid-β (Aβ) and tau pathology, but this protein-centric view does not fully account for early and persistent metabolic, proteostatic, and stress-related disturbances. Emerging evidence points to dysregulated translational control as an early feature of AD. In this context, transfer RNA (tRNA)-derived small RNAs (tsRNAs), including tRNA-derived fragments (tRFs) and tRNA halves, have emerged as regulators of translation, ribosome engagement, and stress adaptation. Many are generated through regulated cleavage and can modulate protein synthesis and proteostasis under oxidative, mitochondrial, or nutrient stress. These functions are particularly relevant to neurons, which depend on precise translational control and are vulnerable to chronic stress. This review discusses tsRNAs in AD and related neurodegeneration, focusing on their molecular heterogeneity, context-specific functions, and links to neuronal stress responses. We propose that selected tsRNAs may represent an underexplored regulatory layer linking chronic cellular stress to maladaptive translational remodeling in AD. Incorporating this layer into current AD frameworks may refine models of RNA dysfunction and inform biomarker and therapeutic development. Chronic stress in Alzheimer’s induces tRNA cleavage to tsRNAs (tRFs/tiRNAs). These modulate translation via ribosomes, stress granules, and proteostasis. Transiently adaptive, persistent stress drives maladaptive translational suppression and proteostatic failure, linking cellular stress to neuronal vulnerability