title: Alzheimer's dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy.
abstract: There is a widely shared view among Alzheimer's disease (AD) investigators that the amyloid hypothesis best describes the pathogenic cascade that leads, ultimately, to neuronal degeneration and irreversible dementia. The most persuasive evidence comes from studies of damaged brains of patients in the late stages of AD and from animal studies that attempt to mimic the hereditary forms of early-onset dementia. Despite this impressive body of knowledge, we still lack the means to either arrest or prevent this horrible contagion. This essay attempts to describe what we know, and do not know, about the earliest stages of the disease, focusing on the possibility that the initial pathological changes involve oxidative-induced inflammatory damage to small blood vessels. The resulting ischemia activates amyloid-processing enzymes and other proinflammatory factors that eventually compromise neuronal functions, leading, over time, to the complex lesions that characterize advanced disease. The idea that blood vessel damage is primary has a long history and many prior advocates. The novel addition offered here is the speculation that low-abundance, gain-of-function somatic mutations of the amyloid precursor protein may be part of the triggering mechanism.
authors.affiliation: Department of Pathology, Boyer Center for Molecular Medicine, Yale University, 295 Congress Ave., P.O. Box 9812, New Haven, CT 06536-0812, USA. vincent.marchesi@yale.edu
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Marchesi
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D000682:Amyloid / Q000378:metabolism*; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D042241:Early Diagnosis; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000682:Amyloid; D017382:Reactive Oxygen Species