Critical to this Review is the Arnsten et al. [86] hypothesis that tau pathology within select projection neurons with susceptible microenvironments can initiate sporadic AD (sAD) and the equally remarkable observation by Braak and Del Tredeci [85] supporting the idea that axons of cortico-cortical top-down neurons in neocortical fields involved in AD are key for carrying and spreading abnormal tau trans synaptically into the distal dendritic segments of nerve cells following directly into the neuronal chain. The gene discussed is MAPT; the disease is Alzheimer disease.