title: On the origin of Alzheimer's disease. Trials and tribulations of the amyloid hypothesis.
abstract: The amyloid cascade hypothesis, which implicates the amyloid Aβ peptide as the pathological initiator of both familial and sporadic, late onset Alzheimer's disease (AD), continues to guide the majority of research. We believe that current evidence does not support the amyloid cascade hypothesis for late onset AD. Instead, we propose that Aβ is a key regulator of brain homeostasis. During AD, while Aβ accumulation may occur in the long term in parallel with disease progression, it does not contribute to primary pathogenesis. This view predicts that amyloid-centric therapies will continue to fail, and that progress in developing successful alternative therapies for AD will be slow until closer attention is paid to understanding the physiological function of Aβ and its precursor protein.
authors.affiliation: Department of Anatomy, Loma Linda University School of Medicine, Evans Hall B08, 24785 Stewart Street, Loma Linda, CA 92354, United States. Electronic address: mcastello@llu.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Castello
authors.affiliation: Department of Anatomy, Loma Linda University School of Medicine, Evans Hall B08, 24785 Stewart Street, Loma Linda, CA 92354, United States. Electronic address: ssoriano@llu.edu.
authors.forename: Salvador
authors.initials: S
authors.lastname: Soriano
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006801:Humans; D009410:Nerve Degeneration; D010641:Phenotype; D058225:Plaque, Amyloid; D012307:Risk Factors; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor
keywords: Alzheimer's disease; Amyloid beta; Neurodegeneration