ticipate in the appropriate circuits? To what degree does adult neurogenesis occur in areas other than the dentate gyrus? In a related fashion, to what degree can the natural process of neurogenesis in the hippocampus be used to replace neurons in a neurodegenerative disorder such as Alzheimer's disease? Obviously it will take time to obtain answers to these questions, but the field is moving rapidly, and we must now incorporate the potential for new neurons into our thinking about malfunctioning neurons and degenerating neurons in the aging brain.

CONCLUDING REMARKS

This report outlines a microscopic and neuroanatomic approach to understanding neurobiological events that underlie memory decline with aging. The available data suggest that the focus of such analyses should be the vulnerable circuit, and the delineation of phenotypic characteristics that render a cell class or circuit selectively vulnerable to aging. With respect to Alzheimer's disease, the key reflection of vulnerability is degeneration, whereas memory decline in the context of normal aging is likely due to subtle neurochemical and morphologic alterations that lead to functional impairment in the absence of frank neuronal degeneration. This differentiation is not absolute, however, in that degenerative events are clearly under way in the entorhinal cortex of neurologically normal elderly people. Many of these neurons appear as "transitional' with respect to degenerative profiles typical of Alzheimer's disease, and it will be critical to focus more attention on these transitional events if we are to adequately differentiate a stable, relatively high-functioning state from the early stages of a progression toward Alzheimer's disease. In addition, much of the work on animal models suggests that functional decline in the context of normal aging or senescence (e.g., age-related memory impairment) is unlikely to be due primarily to neuron loss and is more likely to be a reflection of shifts in gene expression or key neurochemical attributes that impair function in an intact circuit. This suggests that therapy targeted at restoring a youthful phenotype to vulnerable circuits may be particularly effective, and data exist demonstrating the rescue of age-impaired cholinergic and dopaminergic circuits. In addition, replacing dead neurons or impaired circuits through the use of stem cells may be more realistic than previously thought, although obtaining the requisite circuit specificity from such an approach may be problematic. Finally, naturally occurring neurogenesis, particularly in the adult dentate gyrus, offers another avenue for restoration of function, and data exist showing that the generation of new hippocampal neurons and their continued viability are responsive to behavioral and endocrine intervention.

Thus, while conditions such as Alzheimer's disease clearly involve devastating neuron loss, the scenario for normal aging is far more dynamic and



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