We and others have previously observed a robust aberrant accumulation of soluble species of hyperphosphorylated tau within the synaptic compartment in clinically manifest AD brains compared to very small quantities or absence of those in resilient brains with comparable tangle burdens [68, 84], suggesting that soluble pathological species of tau, rather than tau tangles, might be the critical toxic moiety leading to neurodegeneration and clinical expression of AD. This evidence concerns the gene MAPT and Alzheimer disease.