In summary, our findings demonstrate that the activity of the calcium-regulated protease, calpain, is elevated at early Braak stages (II-III), occurring alongside activation of the tau kinases cdk5 and GSK-3, and preceding accumulation of Aβ1-42, increases in phosphorylation of tau at disease relevant epitopes, and loss of synaptic markers at end-stage AD (Fig. 6d). Here, CDK5 is linked to Alzheimer disease.