In conclusion, the present investigation not only highlights a novel dynamic positive feed-forward regulation between APP/Aβ and N-truncated tau in vivo by reinforcing the concept of pathological tau as main therapeutic target of Alzheimer’s disease but also hopefully helps to design more efficacious and safety tau-directed interventions by prospecting the 12A12mAb as beneficial and disease-modifying approach for the cure of Alzheimer’s disease and other tauopathies. Here, APP is linked to early-onset autosomal dominant Alzheimer disease.