THE EU/US TASK FORCE’S FUTURE FOR ANTI-AMYLOID TRIALS: FAITES VOS JEUX

2020 ◽  
pp. 1-2
Author(s):  
L.S. Schneider
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phenotypic Expression ◽  
Amyloid Plaques ◽  
Scientific Investigation ◽  
Amyloid Cascade Hypothesis ◽  
Amyloid Cascade ◽  
The Eu

To be clear, the amyloid cascade hypothesis is well-established, beyond dispute, and ‘alive and well’ as a framework for the scientific investigation of Alzheimer’s disease. Imbalances in amyloid production and clearance occur very early and are seminal factors in the pathophysiology and phenotypic expression of the illness (1, 2). Although we define clinical Alzheimer’s by amyloid plaques, consider aggregates as initiating events, and note that several amyloid-related genotypes are causative or protective, this does not mean that targeting any component of the amyloid cascade necessarily will be therapeutic. Other factors may be at play.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

scholarly journals Fleshing out the amyloid cascade hypothesis: the molecular biology of Alzheimer's disease

2000 ◽  
Vol 2 (2) ◽  
pp. 101-110 ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Biology ◽  
Basic Science ◽  
Amyloid Protein ◽  
Amyloid Cascade Hypothesis ◽  
Protein Tau ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Amyloid Cascade

Alzheimer's disease (AD) is a disorder of two pathologies- plaques and tangles. The former have as a key constituent amyloid protein and the latter the microtubule-associaied protein tau. Genetics has demonstrated that changes in either protein are sufficient to cause dementia. The amyloid cascade hypothesis proposes that plaque-related changes precede tangle-related changes and positions amyloid as central to the degeneration of AD. All the evidence suggests this is correct, including evidence that presenil ins alter the processing of the amyloid precursor protein and evidence that disrupting the normal properties of tau underlies the related froniotemporal dementias. The amyloid cascade hypothesis has provided the basis for nearly a decade of intensive basic science - the skeleton of that hypothesis can now be fleshed out, and confidence is growing that this will result in useful disease-modifying therapies in the future.

scholarly journals Computational Modeling of Catecholamines Dysfunction in Alzheimer’s Disease at Pre-Plaque Stage

2020 ◽  
Vol 77 (1) ◽  
pp. 275-290
Author(s):  
Daniele Caligiore ◽  
Massimo Silvetti ◽  
Marcello D’Amelio ◽  
Stefano Puglisi-Allegra ◽  
Gianluca Baldassarre
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Catecholamine Release ◽  
Therapeutic Interventions ◽  
System Level ◽  
Amyloid Cascade Hypothesis ◽  
Neural Data ◽  
Sequence Of Events ◽  
Amyloid Cascade

Background: Alzheimer’s disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. Objective: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). Methods: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients. Results: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. Conclusion: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.

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