Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca²⁺ signaling pathways responsible for cognition. Hydrolysis of the β-amyloid precursor protein (APP) yields two products that can influence Ca²⁺ signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca²⁺ that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca²⁺ within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca²⁺ being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca²⁺ signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca²⁺ signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca²⁺-dependent protein phosphatase calcineurin. The alteration in Ca²⁺ signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.