MAPT and Alzheimer disease: Indeed, the soluble, intracellular Aβ42 and hyperphosphorylated tau oligomers, and not their aggregated, insoluble counterparts, appear to cause the decrease in synaptic transmission and the eventual death of neurons observed in AD, as these effects appear to occur prior to the formation of senile plaques and NFTs (Mucke et al., 2000; Manczak et al., 2006; Cirrito et al., 2008; Lasagna-Reeves et al., 2011; Polito et al., 2014).