In AD, abnormally elevated CDK5 activity enhances the phosphorylation of its substrates such as APP, tau, and neurofilaments.93 Mechanistically, CDK5 is activated by its neuron-specific and membrane-localized activators p35 and p39, which are cleaved by calpain into p25 and p29, respectively. The gene discussed is CDK5R1; the disease is Alzheimer disease.