title: The senescence hypothesis of disease progression in Alzheimer disease: an integrated matrix of disease pathways for FAD and SAD.
abstract: Alzheimer disease (AD) is a progressive, neurodegenerative disease characterised in life by cognitive decline and behavioural symptoms and post-mortem by the neuropathological hallmarks including the microtubule-associated protein tau-reactive tangles and neuritic plaques and amyloid-beta-protein-reactive senile plaques. Greater than 95 % of AD cases are sporadic (SAD) with a late onset and <5 % of AD cases are familial (FAD) with an early onset. FAD is associated with various genetic mutations in the amyloid precursor protein (APP) and the presenilins (PS)1 and PS2. As yet, no disease pathway has been fully accepted and there are no treatments that prevent, stop or reverse the cognitive decline associated with AD. Here, we review and integrate available environmental and genetic evidence associated with all forms of AD. We present the senescence hypothesis of AD progression, suggesting that factors associated with AD can be seen as partial stressors within the matrix of signalling pathways that underlie cell survival and function. Senescence pathways are triggered when stressors exceed the cells ability to compensate for them. The APP proteolytic system has many interactions with pathways involved in programmed senescence and APP proteolysis can both respond to and be driven by senescence-associated signalling. Disease pathways associated with sporadic disease may be different to those involving familial genetic mutations. The interpretation we provide strongly points to senescence as an additional underlying causal process in dementia progression in both SAD and FAD via multiple disease pathways.
authors.affiliation: Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK, seh66@medschl.cam.ac.uk.
authors.forename: Sally
authors.initials: S
authors.lastname: Hunter
authors.forename: Thomas
authors.initials: T
authors.lastname: Arendt
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
mesh_terms: D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology*; D018450:Disease Progression; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000473:pathology
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