In this chapter, I have promoted viewing Alzheimer's disease as a memory disorder, as opposed to thinking of AD as a generalized neuropathologic dementia. The basic hypothesis is that, for early stages of AD, which are characterized not by generalized dementia but rather by much more subtle deficits in memory consolidation, there will be derangements of the normal signal transduction machinery that underlies memory. This viewpoint sets me apart from most investigators in the AD field. However, I am optimistic that this will be a fruitful avenue of pursuit because the idea is based upon the tremendous advances that have been made in the last decade in our understanding of the basic biochemistry of memory. If this is the case, it also means that AD is likely the area where recent progress in understanding the basic science of memory will translate into an improvement in capacity to attack a clinical disorder of great significance.

Interestingly, as was described in the chapter, several studies have indicated that Ap peptide overproduction in the CNS can elicit cognitive deficits in rodents in the absence of neuronal loss or even Ap deposition into plaques. These findings are consistent with the idea that memory deficits in early stages of AD may be due to disruption of the neuronal signal trans-duction machinery that normally subserves memory formation.

We also talked about the great strides that have been made in identifying the genetic factors contributing to AD. Specifically, we talked about APP, presenilin, and ApoE4 and how mutations or isoforms of these gene products can cause or predispose one to developing AD. I also provided an overview of new mouse models for AD that capitalize upon the human findings in order to allow the generation of model systems of utility in the basic science research laboratory.

The principal unifying theme of the chapter is the amyloid beta hypothesis of AD. To my eye at least, there is a reassuring convergence of many different sorts of data that support the Ap hypothesis of AD. While I did not organize the chapter around evaluating this hypothesis directly, evaluating the contents of the chapter with this question in mind is a useful exercise. Students in particular might find it useful to recast the section on mouse models of AD in terms of evaluating the block, mimic, and measure predictions of the Ap hypothesis.

More than most other areas of contemporary neuroscience research, it seems to me that the AD field is at the intersection of basic and clinical research—a critically important clinical problem in search of answers that only basic science can provide. AD is a disease of human memory. The complexity of AD pathogenesis is rooted in the complexity of memory itself. Hopefully advances in understanding the basic science of memory will soon translate into tangible improvements in treating AD.

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