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I have mentioned already that I think that cell death is a limited process in Alzheimer's disease and I want to focus your attention on the idea that neuronal inactivity and neuronal atrophy might be a major hallmark of Alzheimer's disease, one so far to which we have paid very little attention. There are many pieces of information in the literature that neuronal inactivity is important. There is a lower total amount of protein in the brains of Alzheimer's patients, there are fewer cytoplasmic and messenger RNA's, glucose metabolism is going down, these events are even preceding the clinical symptoms of Alzheimer's disease. Later glucose metabolism in the brain is related to the cognitive deficiency . It is also noted that in ApoE4 homozygous patients at risk, there is a decreased metabolism although there are no clinical symptoms yet.

Our own work on markers for neuronal inactivity shows a very clear decrease in many areas which are affected. As a marker for neuronal activity in postmortem tissue we found that the size of the Golgi apparatus is a very sensitive one. From animal experiments we know that when a neuron is activated the Golgi apparatus becomes bigger. When you inhibit a neuron the golgi apparatus becomes smaller. The same marker can be used in postmortem tissue using antibodies against certain compounds in the Golgi apparatus. Here you can see the nucleus basalis of Meynert in a control patient and you can see around the nucleus the black staining of the nucleus. The nucleus basalis of Meynert was thought to be an example of an area of tremendous cell death in Alzheimer's disease, which is not the case. It's not a loss of neurons but instead a loss of cholinergic markers. The cells are not recognized as big cholinergic neurons because of shrinkage but they are still present. At the same rate that the number of big neurons is decreasing the number of small neurons in increasing. You can see where you stain for the size of the Golgi apparatus that even those neurons that remain large have small Golgi apparatus in the nucleus basalis of Meynert and the other neurons have only a little bit of Golgi apparatus left. So the inactivity can clearly be seen by staining for the size of the Golgi apparatus.