Spreading of Tau Pathology in Sporadic Alzheimer’s Disease Along Cortico-cortical Top-Down Connections

By using AT8-immunocytochemistry that visualizes hyperphosphorylated tau protein, we examined neurofibrillary changes related to sporadic Alzheimer’s disease (AD) in N = 40 individuals at neurofibrillary tangle (NFT) stages I–IV. We report the presence of abnormal tau changes within solitary pyramidal neurons in layers III and V of the neocortex. These pyramidal cells showed pathology in different cell compartments (dendritic, somatic, axonal) that appeared to occur sequentially: Tau pathology was seen in distal segments of the basal dendrites, then in proximal dendrites, the soma, and, finally, in the axon of affected neurons. These findings are remarkable in that they point to the existence of neurofibrillary changes in regions routinely associated with later NFT stages. In addition, they lend support to the idea that it may be the axons of cortico-cortical top-down neurons in neocortical fields involved in AD that carry and spread abnormal tau seeds in a focused manner (transsynaptically) into the distal dendritic segments of nerve cells following directly in the neuronal chain, thereby sustaining further tau-seeded templating.