An evaluation of the amyloid cascade model using in vivo positron emission tomographic imaging

The amyloid cascade hypothesis posits that the accumulation of amyloid β (Aβ) is the triggering factor for Alzheimer's disease, which consecutively induces aggregation of tau, synaptic loss, and cell death. Most experimental and clinical evidence supports this model, but the available data are largely qualitative. Here, we tested the amyloid cascade hypothesis by using in vivo evaluation of positron emission tomography and magnetic resonance imaging.

Path analysis was used to estimate the relationships among Aβ accumulation (PiB standardized uptake value ratio (SUVR)), tau aggregation and its related neuroinflammation (THK5351 SUVR), grey matter atrophy in the medial temporal region, and memory function in Aβ-positive subjects. We also performed additional regression analyses to evaluate the effect of Aβ on the toxicity of tau aggregation/neuroinflammation.

Path analysis supported our hypothesized model: Aβ accumulation affected tau aggregation/neuroinflammation in the medial temporal region, and these pathological changes caused of the grey matter atrophy and memory dysfunction. In separate regression analyses, THK5351 SUVR had a significant effect on grey matter atrophy only in PiB-positive subjects. The analysis of the interaction effect showed that the effects of THK5351 SUVR on grey matter atrophy were significantly different between PiB-positive and PiB-negative groups. When we included the effect of being an apolipoprotein E ε4 carrier as a covariate, the interaction effect remained significant.

Our in vivo evaluation of positron emission tomographic and magnetic resonance imaging data supported the amyloid cascade hypothesis. In addition, it indicated that Aβ not only accelerates tau aggregation/neuroinflammation but promotes its toxicity. Our findings showed the importance of understanding the role and therapeutic potential of the interaction between amyloid and tau aggregation/neuroinflammation in Alzheimer's disease.