Top-Down Projections Direct the Gradual Progression of Alzheimer-Related Tau Pathology Throughout the Neocortex

In sporadic Alzheimer's disease (sAD), tau pathology gradually but relentlessly progresses from the transentorhinal region of the temporal lobe into both the allocortex and temporal high order association areas of the neocortex. From there, it ultimately reaches the primary sensory and motor fields of the neocortex. The brunt of the changes seen during neurofibrillary stages (NFT) I-VI is borne by top-down projection neurons that contribute to cortico-cortical connectivities between different neocortical fields. Very early changes develop in isolated pyramidal cells in layers III and V, and these cells are targets of top-down projections terminating in association areas of the first temporal gyrus or in peristriate regions of the occipital lobe. Neurofibrillary pathology in these regions is routinely associated with late NFT stages. Sequential changes occur in different cell compartments (dendritic, somatic, axonal) of these early-involved neurons. Tau pathology first develops in distal segments of basal dendrites, then in proximal dendrites, the soma, and, finally, in the axon of affected pyramidal neurons. This sequence of abnormal changes supports the concept that axons of cortico-cortical top-down neurons may carry and spread abnormal tau seeds in a focused manner (transsynaptically) into the distal dendritic segments of nerve cells directly following in the neuronal chain, thereby sustaining tau-seeded templating in sAD.