Although numerous aspects of the detailed mechanism of neuronal dysfunction in AD remain unsettled, a broad consensus about some of the principal pathogenic events has been reached by many investigators in the field. Evidence from genetic, neuropathological, cell biology, and animal modeling studies suggests that the gradual accumulation of Aβ42 in limbic and association cortices leads to its aggregation into oligomers, polymers, and amyloid fibrils. These various assemblies—in particular, small diffusible oligomers—appear to be able to induce synaptic and dendritic dysfunction and to activate microglia and astrocytes (representing a local inflammatory reaction). Such changes, first subtle and then increasingly robust, are accompanied by an array of further cellular and biochemical alterations, including altered ionic homeostasis, free radical formation, oxidative injury, neuritic dystrophy, and, ultimately, neuronal death. Because the potential cellular responses to Aβ are myriad and complex, it has been argued that it would be more efficient to decrease the levels of Aβ42 in the brain than to attempt to interfere with 1 or more of these secondary effects of Aβ.