Fig. 1

Anatomical sites of origin and ordered progression of NFT pathology in early sAD. Depiction of the stereotypical site(s) of origin and ordered sequence of progression of pTau pathology throughout the brain, focusing on five neuron populations in the temporal lobe (A) and rostral pons (B) that accumulate pTau in the earliest stages of sAD (i.e., Braak stages I–II and pre-tangle stages). The features that predispose these vulnerable neurons to NFT formation remain elusive. It has been suggested that Tau pathology spreads through synaptically connected neurons; however, discrepancies between connectivity and the distribution of pTau pathology appear to preclude a simple model of connectome-based spread in humans. In this paper we highlight these discrepancies and investigate an alternative hypothesis wherein high expression of a receptor for ApoE (teal shading) predisposes vulnerable neurons to pTau-associated neurodegeneration. A Temporal lobe: purple arrows denote the unidirectional tri-synaptic circuitry underlying memory formation. Red arrows trace the stereotypical progression of pTau pathology in the medial temporal lobe. In Braak stage I, pTau pathology is confined to ErC L2 projection neurons. In Braak stage II, pTau pathology progresses to include the basal lamina of the ProS-CA1 border region. In Braak stages III and IV, pTau pathology progresses throughout the cornu ammonis. Paradoxically, despite being the major synaptic recipient of ErC L2 neurons, dentate granule neurons (light blue arc) are spared from NFT pathology until late-stage sAD (Braak stages V/VI). This contrasting directionality of purple and red arrows indicates that NFT pathology progresses in a direction that is opposite to the synaptic connections underlying memory. Although often overlooked, pTau also accumulates within multiple distal dendritic tips of solitary L3 and L5 pyramids in the temporal neocortex very early in sAD (Braak stage I), while sparing neighboring neurons. B Rostral pons: pTau pathology classically begins in the LC–PC complex (pre-tangle stage a/b) before progressing to raphe nucleus (pre-tangle stage c) and ErC L2 (Braak stage I, see A). LC axonal projections (blue arrow in B5) innervate virtually the entire brain including all layers of temporal neocortex (depicted by blue axon terminals in L1–L6 of temporal cortex). Raphe neurons (green arrow in B4) also project widely throughout the brain. Since LC and raphe axons arborize over large areas and individual projection neurons classically innervate hundreds of neighboring target neurons, selective spread of pTau to ErC L2 neurons and solitary L3/L5 pyramids is not easily reconciled with connectome-based Tau spread