RECENT SCIENTIFIC DEVELOPMENTS

One important line of recent evidence suggests that the mild age-related cognitive decline that occurs in nondemented individuals is different from that occurring in people with Alzheimer's disease and may not be due entirely or even primarily to neuronal loss. The progressive neuronal cell death that is observed in Alzheimer's disease is not characteristic of benign senescent memory loss that occurs frequently with increased aging (Morrison and Hof, 1997; Rapp and Gallagher, 1996; for further discussion and references, see Morrison, Appendix A). In particular, the entorhinal cortex, which displays massive neuronal loss in the brains of patients with advanced Alzheimer's disease, does not undergo any significant neuronal loss with aging in non-demented patients (Morrison, Appendix A). These findings support the hypothesis that the mild memory decline that occurs with age may be due to biochemical shifts in still-intact neural circuitry. Like neuronal loss, these disruptions may involve selective vulnerability in the entorhinal cortex and other brain regions, such as the hippocampus (West, 1993; Peters et al., 1998; Gomez-Isla et al., 1996; Morrison, Appendix A).

If cognitive decline can be attributed even in part to disruptions in the neural network other than cell loss, it is important to identify the responsible mechanisms. Recent research has identified various dynamic processes that occur in the adult brain, indicating that, in general, the brain undergoes more change than previously believed. Among the more dramatic kinds of change that have been observed are increased dendritic growth (Kolb and Whishaw, 1998) and neurogeneration in areas associated with higher cognitive functions (e.g., Gould et al., 1999b). For evidence of lasting changes in the brain as a result of life experiences, see Buonomano and Merzenich (1998), Greenough (1976), Elbert et al. (1995), and Pascual-Leone and Torres (1993). Genetic factors, such as the presence of the APOE-ε4 allele, well known to be associated with Alzheimer's disease, may also influence cognitive outcomes in non-demented older persons. In addition, neural health is likely to be affected by three cellular and molecular processes that contribute to neurodegeneration, in Alzheimer's disease and related dementias: apoptosis (programmed cell death), inflammation (acute phase injury), and the generation of free radicals (oxidative stress). The selective vulnerability of certain brain regions to neuronal loss in dementias is known to match closely with those regions in which these three processes are most active.

Especially intriguing is the fact that although these three processes are implicated in dementia, they are normally beneficial to cognitive functioning: each is involved throughout life in helping to maintain the integrity of healthy neural circuits. Thus, dysfunctions in these processes, even if not leading to cell loss, may provide mechanisms for cognitive decline.

The beneficial functions of apoptosis, inflammation, and free radical re-



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