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. 2011 Feb 7:2011:630865.
doi: 10.4061/2011/630865.

The pathogenesis of Alzheimer's disease: a reevaluation of the "amyloid cascade hypothesis"

R A Armstrong  1
Affiliations

The pathogenesis of Alzheimer's disease: a reevaluation of the "amyloid cascade hypothesis"

R A Armstrong. Int J Alzheimers Dis. .

Abstract

The most influential theory to explain the pathogenesis of Alzheimer's disease (AD) has been the "Amyloid Cascade Hypothesis" (ACH) first formulated in 1992. The ACH proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs) death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1) is there a relationship between the pathogenesis of SPs and NFTs, and (2) what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.

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Figures

Figure 1
Figure 1
Extensive β-amyloid (Aβ) deposition in gyri of the temporal lobe in a case of Alzheimer's disease (AD) (Aβ immunohistochemistry, bar = 1 mm).
Figure 2
Figure 2
The original Amyloid Cascade Hypothesis (ACH) [7]. Aβ: β-amyloid, APOE: apolipoprotein E, APP: amyloid precursor protein, PSEN1/2: presenilin genes 1 and 2, NFTs: neurofibrillary tangles.
Figure 3
Figure 3
A modification of the Amyloid Cascade Hypothesis (ACH). Aβ: β-amyloid, APOE: apolipoprotein E, APP: amyloid precursor protein, PSEN1/2: presenilin genes 1 and 2, NFTs: neurofibrillary tangles, and SPs: senile plaques.
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