In conclusion, we have provided multiple lines of supporting evidence that the ZDHHC21 p.T209S mutation contributes to AD by enhancing the palmitoylation of APP and FYN, impairing the synapses, and aggravating Aβ pathology, tau hyperphosphorylation, and neuronal loss, ultimately causing cognitive impairment in mice. Here, ZDHHC21 is linked to Cognitive impairment.