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There is an urgent need for treatments for sporadic Alzheimer’s Disease (sAD). Although antibodies removing ß-amyloid have recently been shown to slow disease progression, the degenerative course continues. Thus, there is a need for strategies that intervene early in the degenerative process, before irreversible damage is done to neurons (e.g., by autophagic degeneration). This review will summarize the evidence indicating that targeting calpain-2 with a selective inhibitor might represent a novel strategy for the treatment of sAD. Calpains are neutral proteases that are activated by intracellular calcium. The two main isoforms are calpain-1, which is activated by low, micromolar levels of calcium and generally has beneficial effects for cellular health, and calpain-2, which is activated by high, almost millimolar levels of calcium and mediates many of calcium’s toxic actions. Calcium signaling becomes dysregulated with advancing age due to loss of regulatory proteins such as calbindin, and is pronounced in sAD brain tissue, including signs of calcium leakage from the smooth endoplasmic reticulum (SER) through phosphorylated ryanodine receptors (pRyR2). Both calpain-1 and calpain-2 are elevated in AD brains and herald the rise in tau pathology, but only calpain-2 is localized with neurofibrillary tangles (NFTs) and pretangles. Calpain drives a spectrum of AD-related pathologies, and in particular, calpain drives tau hyperphosphorylation by cleaving, and thus disinhibiting, kinases central to tau hyperphosphorylation, i.e., GSK3β and cdk5, as well as increasing Aβ formation and autophagic degeneration. Thus calpain-2 inhibitors may reduce a spectrum of sAD pathology, protecting neurons at very early stages of disease.