tex in early Alzheimer's disease and progress through the circuit as the disease progressed, suggestive of a transsynaptic mechanism of propagation. The stimulus/agent is, of course, unknown.

In summary, I suggest that a separation of mechanisms may occur in the evolution of Alzheimer's disease. These stages may parallel various clinical stages. The relatively flat progression has been referred to as successful aging, optimal aging, etc. The initiation phase may be similar to the phase called mild cognitive impairment. The propagation phase may be the entry into Alzheimer's disease and related dementias. Of course, the correlation between brain changes and functional state is challenging due in no small part to the reserves and functional plasticity of circuits, particularly in the successful aging and initiation phases. Thus, for example, it would be anticipated that changes that occur in the initiation phase are subclinical for many measures, even though from a mechanistic viewpoint these changes are signatures of progression.

The implication of this concept is that it suggests that different therapeutics will be necessary to abort or slow the mechanism, depending on the stage of progression. Thus the initiation phase may be amenable to such interventions as nonsteroidal anti-inflammatory drugs, estrogen, education, antioxidants, etc. The later propagation phase may be much less sensitive or even insensitive to such interventions, although there is evidence to suggest that antioxidants such as Vitamin E can modulate progression at this point.

THE INITIATION PHASE AND EARLY EVENTS IN A PATHOLOGICAL CASCADE

To study the initiation phase in vitro or in vivo, it is necessary to develop a model in which subthreshold insults occur that do not cause overt cell death but rather impair cellular function. An appropriate stimulus to promote cell dysfunction is Aβ, since this neurotoxic protein accumulates in the form of senile plaques in the aged human and canine brain. Exposing cell cultures to sufficient levels of Aβ causes cell death in neurons and glia (see Cotman et al., 1999, for a review). Neurons die by initiating programmed cell death pathways, the up-regulation of pro-apoptotic proteins or the down-regulation of anti-apoptotic proteins (Paradis et al., 1996). To identify events associated with the initiation phase, we are now using subthreshold levels of Aβ that do not cause overt neuronal death to determine the sequence of events that occur early in response to an injury. These events may be subtle indicators of neuron dysfunction that develops prior to the classic forms of pathology found in the aged brain, such as senile plaques, neurofibrillary tangles, and cell death. Once neurons are exposed to a potentially toxic stimulus, signal transduction pathways are activated that initiate a cascade of events leading to neuronal dysfunction. This hypothesis led us to examine the role of signal



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