Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer's disease

The etiology of the common, sporadic form of Alzheimer's disease (sAD) is unknown. We hypothesize that tau pathology within select projection neurons with susceptible microenvironments can initiate sAD. This postulate rests on extensive data demonstrating that in human brains tau pathology appears about a decade before the formation of A beta plaques (A beta ps), especially targeting glutamate projection neurons in the association cortex. Data from aging rhesus monkeys show abnormal tau phosphorylation within vulnerable neurons, associated with calcium dysregulation. Abnormally phosphorylated tau (pTau) on microtubules traps APP-containing endosomes, which can increase A beta production. As A beta oligomers increase abnormal phosphorylation of tau, this would drive vicious cycles leading to sAD pathology over a long lifespan, with genetic and environmental factors that may accelerate pathological events. This hypothesis could be testable in the aged monkey association cortex that naturally expresses characteristics capable of promoting and sustaining abnormal tau phosphorylation and A beta production.

Automated summary

The etiology of common, sporadic Alzheimer's disease is unknown. The hypothesis proposed here suggests that tau pathology within specific projection neurons in susceptible microenvironments may initiate sAD, supported by data showing tau pathology appearing a decade before A beta plaques and targeting glutamate projection neurons.