Cyclin towards, or away from, dementia?

The two papers in this debate agreed about data and differed sharply about interpretation – not an unusual situation in science in general nor in the world of Alzheimer disease research. Extensive reports document the presence of aberrant levels of “cell cycle” proteins in AD brain. Key references are listed in Table 1 of the article by Bowser and Smith. The occurrence of the Alz-50 antigen in AD brain is in accord with these data, albeit indirectly. Alz-50 normally occurs in developing brain where cells are progressing through the cell cycle. The question is not whether “cell cycle” proteins are there but whether they play an important role in the pathophysiology of Alzheimer disease. Herrup and Arendt argue forcefully that they do. These authors point out that putting a post-mitotic cell, and specifically a neuron, back into the cell cycle from Go leads the cell to die an apoptotic death. Their argument can be simplified to the following. (1) Putting a post-mitotic neuron back into the cell cycle kills it. (2) Cell cycle proteins occur in increased amounts in Alzheimer brain. (3) Therefore, putting post-mitotic neurons back into the cell cycle is a major cause – perhaps the major cause – of premature neuronal death in Alzheimer disease. Bowser and Smith, in contrast, propose that the cell cycle proteins found in Alzheimer brain are involved in the aberrant cell signaling that is well known to occur in Alzheimer brain. They draw attention to plausible although speculative mechanisms by which the abnormalities in cell cycle proteins described in AD brain could be linked to aspects of cellular abnormalities that occur in this diseased tissue. Clearly, more data are needed to resolve this issue. Specifically, more direct data are needed. Both Herrup and Arendt and also Bowser and Smith frame their arguments significantly by analogy. Both take the same observation and say what can happen. What is needed is direct data to show what does happen, in the brain cells of Alzheimer victims. The solidity of the basic data on cell cycle proteins in Alzheimer brain certainly calls for funding of appropriate proposals to examine the implications of this finding at a more mechanistic level. Until such data are available, a conservative attitude toward both proposals is “very interesting but unproven”. Many, many things have gone wrong in AD brain by the time patients die and come to autopsy. The problem is not finding pathophysiologically plausible abnormalities. Rather, the current problem is to demonstrate by direct experiments which of the abnormalities in AD brain actually contribute in important ways to the brain damage, thereby leading to the clinical signs and symptoms. In this regard, it is important to note that perhaps half of patients above the age of 85 who die with the full-blown Alzheimer neuropathology were not clinically demented during life. A cognitively intact Nun died at 101 with full Alzheimer neuropathology at autopsy. The proposal that the people with asymptomatic Alzheimer neuropathology “would have developed dementia if they had lived long enough” is not only unproven but also untestable. How can one test what would have happened to people if they had lived longer? How old would they have had to become in order to develop clinical dementia? After age 85, they