Fig. 4

Enigmatic aspects of the ACH. This schematic illustrates some of the gaps in our knowledge regarding certain aspects of the ACH. Uncertainty remains about how Aβ aggregate accumulation drives downstream changes. Similarly, there is uncertainty regarding how tau accumulation leads to neurodegeneration. It is likely that the mechanism that link Aβ and tau together and to neurodegeneration are complex. One concept that is not commonly discussed is that the presence of either amyloid or tau pathology and both pathological and compensatory response may make the brain more vulnerable to additional insults. Such vulnerability might explain why clinical progression is so variable, and how co-morbidities may impact the clinical phase of disease