CAPN2 and Alzheimer disease: However, considering both the facts that i) loss of synapse function, structure and morphology is among the earliest events in AD pathogenesis, occurring much before behavioral and pathological symptoms1,2,28 and ii) calpain is a critical regulator of synapse function and plasticity4,29, we now demonstrate that synaptosomal calpain-2 activity and protein levels increase very early in a synapse-specific manner.