Amyloid is essential but insufficient for Alzheimer causation: addition of subcellular cofactors is required for dementia

International Journal of Geriatric Psychiatry
Jeffrey Fessel

Abstract

The aim of this study is to examine the hypotheses stating the importance of amyloid or of its oligomers in the pathogenesis of Alzheimer's disease (AD). Published studies were examined. The importance of amyloid in the pathogenesis of AD is well established, yet accepting it as the main cause for AD is problematic, because amyloid-centric treatments have provided no clinical benefit and about one-third of cognitively normal, older persons have cerebral amyloid plaques. Also problematic is the alternative hypothesis that, instead of amyloid plaques, it is oligomers of amyloid precursor protein that cause AD.Evidence is presented suggesting amyloid/oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, requires the addition of cofactors known to be associated with AD. Those cofactors include several subcellular processes: mitochondrial impairments; the Wnt signaling system; the unfolded protein response; the ubiquitin proteasome system; the Notch signaling system; and tau, calcium, and oxidative damage. A modified amyloid/oligomer hypothesis for the pathogenesis of AD is that activation of one or more of the aforementioned cofactors creates a burden of functional impairments that, in co...Continue Reading

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Citations

Mar 3, 2018·Brain Imaging and Behavior·Cristina LoisJulie C Price
Nov 26, 2019·Alzheimer's & Dementia : Translational Research & Clinical Interventions·Jeffrey Fessel
Jan 6, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vladimir KhavinsonSvetlana Trofimova
Feb 19, 2021·Alzheimer's & Dementia : Translational Research & Clinical Interventions·Jeffrey Fessel
May 18, 2021·Journal of Alzheimer's Disease : JAD·Kok Pin NgUNKNOWN Alzheimer’s Disease Neuroimaging Initiative

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