The most popular hypothesis on the pathogenesis of Alzheimer's disease is still Selkoe's hypothesis on the primary role of amyloid. The idea that amyloid either from neurons or coming from blood vessels accumulates in the neuropil, is neurotoxic and causes damage to the skeletal proteins and cause dystrophic neurites, neuropil threads, tangles, plaques and ultimately cell death. If amyloid was the cause of Alzheimer's disease, why would Alzheimer's disease be so heterogeneous? It is heterogeneous by area, by patient and there are also typical cases of Alzheimer's disease in which only one particular element is seen as compared to the rest.

What I want to tell you is that the amyloid cascade hypothesis is probably not true. It cannot be such that everything is caused by amyloid, causing pre-tangles as stained by ALZ-50 for instance and the neuropil threads, neurofibrillary tangles, neuritic plaques and cell death. Instead I want to give some evidence that all of those changes that are in fact so typical of Alzheimer's disease are in fact independent phenomena. There are areas where you can see amyloid but other areas where you can see pre-tangles or tangles or plaques. Cell death is in my opinion an overestimated cause of Alzheimer's disease in that it is occurring in some places, CA1 and the locus coeruleus, but not in many others. We can also wonder if the independent phenomena are indeed epiphenomena in that they may not be causal in the clinical symptoms, in the dementia itself. It's just what we see under the microscope -- what we use for diagnostic purposes. But it's very questionable whether the classical phenomena are the cause of the clinical changes we see.