A pathway to Alzheimer's disease (AD) relevant to sporadic AD pathogenesis is described that involves the early and progressive activation of proteolytic systems including, but not limited to, the calpain-calpastatin and endosomal-lysosomal systems. Activation of these proteolytic systems is initiated by normal brain aging and is propelled by the genetic and environmental factors known to increase AD risk. Recent studies show how cathepsins and calpains, acting directly or indirectly through other proteolytic pathways and cellular signaling cascades, may promote beta-amyloidogenesis, neurofibrillary pathology, as well as mediate neurodegeneration in AD.