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This postulate rests on extensive data demonstrating that in human brains tau pathology appears about a decade before the formation of A\u03b2 plaques (A\u03b2ps), 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\u2010containing endosomes, which can increase A\u03b2 production. As A\u03b2 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\u03b2 production.<\/jats:p>","DOI":"10.1002\/alz.12192","type":"journal-article","created":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T14:39:35Z","timestamp":1603118375000},"page":"115-124","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":349,"title":["Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer's disease"],"prefix":"10.1002","volume":"17","author":[{"given":"Amy F. 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