Ribosome impairment, tau alternative splicing, and stress granules: a convergent axis of neuronal vulnerability driving Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the pathological aggregation and deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. However, accumulating evidence points at the disruption of RNA metabolism and translational control as central players in the disease progression. Emerging studies suggest that pathogenic mechanisms previously considered separately-namely ribosome biogenesis impairment, dysregulation of tau alternative splicing, and persistent stress granule (SG) formation-could be components of an integrated axis of neuronal vulnerability contributing to early AD pathogenesis. In AD, ribosomal loss and rDNA transcriptional silencing correlate with tau hyperphosphorylation and tau-ribosome interaction, while SG-mediated sequestration of splicing factors may exacerbate 3R/4R tau imbalance, promoting aggregation-prone isoforms. These processes appear to mutually reinforce through neuroinflammation and chronic translational stress, driving progressive proteostatic failure and cognitive decline. Converging evidence across systems (histopathological, in vivo and in vitro models) strongly suggest the existence of a ribosome-tau splicing-SG axis that operates at a pre-aggregative phase of the disease. In this context, this early disruption of translational homeostasis may trigger neuronal vulnerability decades before Aβ and tau aggregation as well as symptomatic disease. In this review, we synthesize current evidence supporting a stepwise, feed-forward model that links ribosome dysfunction, splicing alterations, and chronic SG persistence in AD. Our hypothesized integrated framework highlights potential pharmacological routes each capable of targeting distinct pathogenic nodes of the axis to restore translational homeostasis and reduce neuronal vulnerability, thus outlining potential upstream intervention strategies beyond the traditional Aβ- and tau-centric therapeutic approaches.