Here, we showed that SRRM2 phosphorylation at Ser1068 increases at the early stage of AD pathology associated with the translocation of SRRM2 to the cytoplasm, destabilizes the spliceosome component PQBP1, broadly affects RNA splicing of synapse genes, and eventually leads to cognitive impairment. This evidence concerns the gene PQBP1 and Alzheimer disease.