Explique clairement et précisément ce paragraphe concernant le modèle de la cascade amyloïde de la maladie d'Alzheimer : Although there is evidence supporting the amyloid hypothesis, there is equally compelling evidence that does not support it, at least in the way that it is currently articulated. The amyloid hypothesis predicts that tau deposition will not happen in the absence of amyloid, A−T + individuals should be, at most, rare, tau should colocalize with amyloid, A+T + individuals should invariably develop neurodegenerative changes and cognitive impairment, and anti-Aβ and anti-tau treatments should halt or greatly slow the progression of neurodegeneration and cognitive impairment. The following sections provide evidence against these predictions and, in consequence, falsify the current articulation of the amyloid hypothesis. Reports of tau positivity in the absence of amyloid.—As previously mentioned, the observed prevalence of A−T + individuals is low if the established stringent cut- offs for tau positivity are applied. However, with use of more liberal cut-offs, earlier regions of interest (for example, tau deposition limited to the transentorhinal region or Braak stage I/II) or more sensitive tau positron emission tomography tracers, the presenceof A−T + has been found in up to 45% of individuals without dementia50,54,55 This condition is referred to as ‘primary age- related tauopathy’56 and is sometimes considered a variant of AD57, undermining the initiating role of Aβ in the cascade. At odds with the findings of imaging studies, which have generally been taken to indicate that Aβ deposition precedes tau deposition, neuropathology studies have supported the opposite sequence. Large cross- sectional autopsy studies have shown that tau pathology is found at young ages (that is, 21–40 years), when Aβ plaques are absent, in the brainstem and locus coeruleus; this pathology then expands into further subcortical nuclei and the entorhinal cortex. In these studies, individuals exhibiting only Aβ plaques in the absence of neurofibrillary tangle pathology were in a minority compared with individuals with tau pathology lacking Aβ deposition58,59. This finding argues against a deterministic model in which Aβ is the cause of tau pathology. Rather, this finding is consistent with the notion that pre-existing age-related tauopathy is a prerequisite for Aβ to act as driver for the spread of tau to the neocortex59. This may also explain why even people with autosomal dominant AD, in which the overproduction and deposition of Aβ are substantial, do not develop symptoms before 30–60 years of age. Indeed, this is the age when a considerable proportion of individuals exhibit age-related tau deposition mainly in the transentorhinal and entorhinal cortex of the medial temporal lobe58 . In mutant APP transgenic mice that overexpress Aβ, severe Aβ plaque pathology is not accompanied by significant tau or neurofibrillary tangle pathology60–62. Indeed to promote accelerated tau pathology by Aβ in transgenic mice, a minimum of pre- existing tau pathology, as present in double Aβ and tau transgenic animals, is required20. Recently, a molecular link between Aβ and tau was identified, namely the cellular prion protein (PrPC). In animal and cellular models, binding of Aβ and p- tau to PrPC is associated with accelerated spreading of tau pathology, which leads to toxic effects22,63. In humans, both Aβ and p- tau bind to PrPC22. As PrP knockdown in APP transgenic mice leads to improved performance of the animals in cognitive tests64, the critical involvement of proteins other than just Aβ argues against the pathogenesis of AD being driven solely by Aβ.