A critical analysis of the ‘amyloid cascade hypothesis’

Abstract

A b s t r a c t The 'amyloid cascade hypothesis' (ACH) is the most influential model of the pathogenesis of Alzheimer's disease (AD). The hypothesis proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD, leading to the formation of extracellular senile plaques (SP), tau-immunoreactive neurofibrillary tangles (NFT), neuronal loss, and ultimately, clinical dementia. Ever since the formulation of the ACH, however, there have been questions regarding whether it completely describes AD pathogenesis. This review critically examines various aspects of the ACH including its origin and development, the role of amyloid precursor protein (APP), whether SP and NFT are related to the development of clinical dementia, whether Aβ and tau are 'reactive' proteins, and whether there is a pathogenic relationship between SP and NFT. The results of transgenic experiments and treatments for AD designed on the basis of the ACH are also reviewed. It was concluded: (1) Aβ and tau could be the products rather than the cause of neurodegeneration in AD, (2) it is doubtful whether there is a direct causal link between Aβ and tau, and (3) SP and NFT may not be directly related to the development of dementia, (4) transgenic models involving

Alzheimer’s amyloid-β peptide disturbs P2X7 receptor-mediated circadian oscillations of intracellular calcium

“…One of the main neuropathological hallmarks of this disease is the deposition of extracellular senile plaques containing amyloid-β (Aβ) peptides, derived from processing of the amyloid-β precursor protein (APP) [3,18]. Many previous data point out to a critical role for deregulation of calcium (Ca 2+ ) homeostasis in the pathogenesis of AD.…”

Combined use of biochemical and volumetric biomarkers to assess the risk of conversion of mild cognitive impairment to Alzheimer’s disease

“…Although "amyloid cascade hypothesis" has given rise to doubts [2], diagnostic criteria of MCI from 2011 indicate the important role of biomarkers [1]. Biomarkers can improve the prediction of MCI conversion to AD.…”

Carbon Monoxide and Iron Modulate Plasmatic Coagulation in Alzheimer’s disease

“…In addition to the recently reviewed, original 'amyloid cascade hypothesis' [1], the development and progression of AD have been associated with viral infection [2], vascular damage from pulse pressure [3], regional deposition of metals, such as iron, resulting in oxidant injury [4][5][6][7][8], metabolic syndrome and morbid obesity [8][9][10], and long term exposure to spontaneous cerebral microemboli [11,12]. Of these various paradigms, the notion that spontaneous emboli, most likely due to systemic hypercoagulability, is of particular interest.…”

“…Alzheimer's disease (AD) is a major source of morbidity and mortality for millions of people worldwide, and intense investigation has led to multiple etiological constructs contributing to AD [1][2][3][4][5][6][7][8][9][10][11][12]. In addition to the recently reviewed, original 'amyloid cascade hypothesis' [1], the development and progression of AD have been associated with viral infection [2], vascular damage from pulse pressure [3], regional deposition of metals, such as iron, resulting in oxidant injury [4][5][6][7][8], metabolic syndrome and morbid obesity [8][9][10], and long term exposure to spontaneous cerebral microemboli [11,12].…”