In the largest postmortem study of autopsied individuals alm

In the largest postmortem study of 3618 autopsied individuals, almost 75% of the individuals without Aβ pathology already harbored cortical NFT pathology mostly confined to the medial temporal regions (Murray et al., 2015). In Braak's study of 2366 autopsied individuals (Braak and Del Tredici, 2014), 95% of the individuals without Aβ pathology had hyperphosphorylated tau pathology, and 94% of individuals harboring tau pathology in the absence of Aβ pathology were stage 1a/1b (19%) and I/II (75%). There were no individuals who exhibited cortical Aβ without any degree of tau pathology (Braak and Del Tredici, 2014). Taken together, these neuropathological studies clearly show the precedence of abnormal tau in the medial temporal regions over cortical Aβ pathology, and tau pathology may be less likely to spread to a significant extent beyond the medial temporal regions without Aβ, although a large scaled 18F-flortaucipir PET study showed possibility of tau deposition in the extra-medial temporal association cortices even without Aβ (Lowe et al., 2018). In the present study, tau deposition in the entorhinal BQ-123 preceded cortical Aβ, and in the medial temporal regions tau deposition preceded Aβ. This finding closely resembles the results of postmortem studies, and we can hypothesize that tau spreads locally without Aβ within the medial temporal cortex. In Braak's series, the frequency of cortical Aβ pathology increased with the advancement of tau stages (8% in stage 1a-1b, 39% in stage I-II, 77% in stage III-IV, and 100% in stage V-VI) (Braak and Del Tredici, 2014). Likewise, the proportion of individuals with NFT stage higher than III steadily increased with the advancement of Thal's Aβ phase (3% in phase 0, 8% in phase 1, 11% in phase 2, 24% in phase 3, 59% in phase 4, and 94% in phase 5) (Murray et al., 2015). The increase in Aβ pathology in the higher tau stages suggests a potential interaction between Aβ and tau. Our study showed that Aβ deposition precedes tau in most of the neocortex above the inferior temporal cortex. If tau plays an important role in the Aβ deposition, tau has to accumulate in the neocortex before the rise in Aβ accumulation. We may thus suspect that Aβ promotes the tau deposition and the appearance of massive tau deposition in the distant cortical areas. Aβ dimers both synthesized and extracted from AD brain specimens induced hyperphosphorylation of tau and neuritic degeneration (Jin et al., 2011). The injection of human amyloid plaque cores into the hippocampus of rat brains also induced severe neuronal loss and markedly increased silver-positive dystrophic neurites (Frautschy et al., 1991). Similarly, the accumulation of NFTs in the amygdala of P301L tau transgenic mice was dramatically increased by injection of synthetic Aβ42-fibrils into the hippocampus (Gotz et al., 2001). Transgenic mouse models expressing both pathological tau and Aβ have also replicated these findings. Greatly increased NFT pathology was observed in double mutant mice with both P301L tau and amyloid precursor protein with Swedish mutation ([APPsw] mutation, K670N and M671L) when compared to single mutant mice with the P301L tau mutation (Lewis et al., 2001). Moreover, the appearance of higher NFT stages was brought forward with a greater consistency of progression in the double mutant mice with P301S tau and V717F APP mutation compared to the transgenic mice with a monogenic P301S tau mutation (Hurtado et al., 2010). Another transgenic mouse model with tau, APP, and presenilin-1 gene mutations showed a more rapid propagation of tau pathology to the more distant brain regions compared to single mutant mice with the tau mutation (Pooler et al., 2015). In contrast, Aβ load was largely unaffected by additional tau mutations and resulting tau accumulation (Hurtado et al., 2010, Lewis et al., 2001). This evidence supports the notion of Aβ-induced acceleration of pathological tau accumulation and propagation. Therefore, we may hypothesize that Aβ may be required for massive deposition of tau in the neocortical areas distant from the medial temporal cortex.