The Spatial Patterns of Plaques and Tangles in Alzheimer's Disease Do Not Support the 'Cascade Hypothesis'

Armstrong, Richard A.; Myers, D.; Smith, C. U. M.

doi:10.1159/000107291

Cited by 21 publications

(29 citation statements)

References 12 publications

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“…The best evidence for a central role of tau in AD pathogenesis was the result of a series of studies by Heiko and Eva Braak and colleagues that demonstrated a progressive sequence of neurofibrillary pathology illustrating the spread of NFT in the CNS [18]. This work established a timeline for NFT lesion progression through the CNS in AD that was tightly correlated to the initial presentation and progression of clinical symptoms [46,47]. This "Braak pattern" of NFT development begins in the limbic cortex of the temporal lobe and progresses to association (polymodal) areas of the neocortex, leaving primary sensory and motor areas unaffected until end stage disease has set in.…”

Section: Tau -The Amyloid Cascade Hypothesis Is Incompletementioning

confidence: 99%

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Bhatia

Hall

2013

Translational Neuroscience

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Recent investigations into the etiology and pathogenesis of Alzheimer's disease (AD) in the past few years have expanded to include previously unexplored and/or disconnected aspects of AD and related conditions at both the cellular and systemic levels of organization. These include how AD-associated abnormalities affect the cell cycle and neuronal differentiation state and how they recruit signal transduction, membrane trafficking and protein transcytosis mechanisms to produce a neurotoxic syndrome capable of spreading itself throughout the brain. The recent expansion of AD research into intercellular and new aspects of cellular degenerative mechanisms is causing a systemic re-evaluation of AD pathogenesis, including the roles played by well-studied elements, such as the generation of Aβ and tau protein aggregates. It is also changing our view of neurodegenerative diseases as a whole. Here we propose a conceptual framework to account for some of the emerging aspects of the role of tau in AD pathogenesis.

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Section: Tau -The Amyloid Cascade Hypothesis Is Incompletementioning

confidence: 99%

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Bhatia

Hall

2013

Translational Neuroscience

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“…The ACH is often regarded as the 'conclusive model' of the aetiology of early-onset FAD, and sporadic AD (SAD), a more complex disorder caused by a variety of factors, but resulting from essentially the same pathological cascade [42,127]. Since its publication there have been observations difficult to reconcile with the ACH and concerns whether it completely describes AD pathogenesis [11,90]. First, transgenic mice, in which genes overexpress amyloid precursor protein (APP), do not reproduce the predicted cascade [39,90].…”

Section: Introductionmentioning

confidence: 99%

“…First, transgenic mice, in which genes overexpress amyloid precursor protein (APP), do not reproduce the predicted cascade [39,90]. Second, SP and NFT are separated in brain both spatially [11] and temporally [39,82] questioning the pathogenic link between them. Third, Aβ and tau could be the reactive products of neurodegeneration rather than their cause, arising as a consequence of oxidative stress [126].…”

Section: Introductionmentioning

confidence: 99%

A critical analysis of the ‘amyloid cascade hypothesis’

Armstrong¹

2014

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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

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“…Studies have also suggested that SP and NFT occur in distinct but independently distributed patterns in AD [19,93]. Studies of the spatial patterns of SP and NFT show them to be clustered, the clusters often being regularly distributed parallel to the pia mater [8].…”

Section: Appmentioning

confidence: 99%

Review article What causes alzheimer’s disease?

Armstrong¹

2013

182

119

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A b s t r a c t Since the earliest descriptions of Alzheimer's disease (AD), many theories have been advanced as to its cause. These include: (1) exacerbation of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3) an environmental factor such as exposure to aluminium, head injury, or malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes and allelic variation in apolipoprotein E (Apo E), (5) mitochondrial dysfunction, (6) a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these theories and concludes that AD is a multifactorial disorder in which genetic and environmental risk factors interact to increase the rate of normal aging ('allostatic load'). The consequent degeneration of neurons and blood vessels results in the formation of abnormally aggregated 'reactive' proteins such as b-amyloid (Ab) and tau. Gene mutations influence the outcome of age-related neuronal degeneration to cause early onset familial AD (EO-FAD

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The Spatial Patterns of Plaques and Tangles in Alzheimer's Disease Do Not Support the 'Cascade Hypothesis'

Cited by 21 publications

References 12 publications

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

A critical analysis of the ‘amyloid cascade hypothesis’

Review article What causes alzheimer’s disease?

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