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The amyloid cascade hypothesis describes a relatively linear, deterministic sequence of events triggered by a gain of A\u03b2 peptide fragment toxicity that results in neurodegeneration and cognitive loss, yet well designed immunotherapy and beta secretase inhibitor trials that have successfully targeted A\u03b2 have failed to have any consistent effects on the steady decline of cognition.<\/jats:p><\/jats:sec><jats:sec><jats:title>New\/updated hypothesis<\/jats:title><jats:p>Mutations of the APP and presenilin genes not only alter the ratio of longer to shorter A\u03b2 fragments (resulting in a gain of A\u03b2 toxicity), but also disrupt the normal homeostatic roles of their respective proteins. The evolutionary history, physiological importance, and complexity of the APP and presenilin systems, as well as other critical components including tau and apolipoprotein E (APOE) imply that altered function of such systems could have severe consequences that include but need not be limited to a gain of A\u03b2 toxicity and would more generally result in altered homeostasis of APP\u2010related functions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Major challenges addressed by our hypothesis<\/jats:title><jats:p>Challenges that a loss of APP homeostasis addresses better than the more limited gain of A\u03b2 toxicity model include the topographic mismatches between A\u03b2 and tau pathology, the profile and chronology of cognitive and biomarker changes that precede the clinical expression of mild cognitive impairment and dementia, and the disappointments of A\u03b2 targeted therapeutics among others.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linkage to other major theories<\/jats:title><jats:p>The importance of APP, \u03b1\u2010 and \u03b2\u2010secretases, the presenilins and \u03b3\u2010secretase, as well as tau was recognized by the authors of the amyloid cascade hypothesis, and has since led multiple investigators to propose alternative, more balanced hypotheses including reduced homeostasis and frank loss\u2010of\u2010function of key components that include but go beyond the currently envisioned linear model of A\u03b2 toxicity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.12124","type":"journal-article","created":{"date-parts":[[2020,6,27]],"date-time":"2020-06-27T03:31:48Z","timestamp":1593228708000},"page":"1582-1590","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["An agnostic reevaluation of the amyloid cascade hypothesis of Alzheimer's disease pathogenesis: The role of APP 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