APOE4 disrupts the central dogma by arresting neuronal proteome dynamics

Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic human iPSC-derived APOE3 and APOE4 neurons and found that APOE4 fundamentally impairs neuronal proteome renewal. Although transcriptional changes were modest, apoE4 disrupted ribosome occupancy, altered translational dynamics, and uncoupled protein abundance from transcript levels.

Proteome-wide turnover measurements revealed a global extension of protein half-lives and widespread accumulation of long-lived proteins. Functional proteomic analyses demonstrated concurrent lysosomal and proteasomal impairments associated with reduced proteasome activity and increased association of APOE with neuronal proteasomes. Longitudinal proteomics further showed that protein accumulation emerges during neuronal maturation and precedes a senescence-like cellular stress state.