The amyloid cascade hypothesis (revisited):

Tau is upstream the amyloid cascade (Delacourte et al, 2002, Brain Aging, issue of June).

A: Neurofibrillary degeneration (NFD) corresponds to the intraneuronal accumulation of tau proteins into PHF (Paired Helical Filaments). PHF are composed of a triplet of abnormally phosphorylated Tau proteins, named "Tau 60, 64, 69" or PHF-Tau.

B: Tau pathology occurs frequently in aging brains, and specifically in the hippocampal region. Degenerating neurons die. Dead neurons are digested by glial cells (astrocytes and microglia).

C: Tau pathology precisely starts in the transentorhinal cortex and tends to spread in the entorhinal cortex and then in the hippocampus

D: APP dysfunction and/or Aß neurotoxicity (E) accelerate NFD so that it will spread in association cortical areas

F: The degenerating process progressively overcomes neuronal plasticity (repair, compensation), to provoke a progressive cognitive decline. 

Remarks:

APP DYSMETABOLISM AND AMYLOIDOSIS

D: Pathological mutations on APP, PS1, PS2 genes teach us that APP dysfunctions are directly linked to AD etiology. They provoke an aberrant catabolism, leading to an overproduction of Aß peptide, mostly 1-42 species. Aß peptides aggregate into amyloid plaques, under the influence of co-factors such as ApoE, complement, antiproteases, proteoglycan, etc. Amyloid plaques accumulate in the cortical grey matter.

In non-familial AD (99% of all cases), it is likely that there are also APP defects, since amyloid lesions are also observed, in similar quantities and distribution.

NEUROFIBRILLARY DEGENERATION

C: NFD invades the cortical areas along a precise, sequential, hierarchical pathway. Cognitive impairment is observed when the hippocampus, the temporal cortex as well as association brain areas are affected. 

The dynamic of NFD spreading is modulated by accelerating factors (inflammation, apoE E4, oxidative stress) ou neuroprotectants (estrogens, anti-oxidants, anti-inflammatory drugs, neurotrophic factors, ApoE E2, etc).