the overall aging process. The literature discussed in support of this hypothesis has been limited due to space constraints and thus some citations may have been unintentionally omitted.

BRAIN AGING, A MULTIPHASE PROCESS: INITIATION AND PROPAGATION PHASES

Several investigators have suggested that Alzheimer's disease may represent an accelerated decline of the normal processes of brain aging. Thus, for example, the normal aged brain appears to accumulate plaques and tangles. This hypothesis suggests that Alzheimer's disease then is simply a further progression in the accumulation of these hallmarks and that relative risk factors would determine the nature of when and how fast accumulation and cognitive decline occur. Hence, all individuals would be subject to the same basic mechanism, and only the rate constant would differ with aging. While this hypothesis is one possibility at a mechanistic level, it is imprecise and does not address the current body of data suggesting that Alzheimer's disease results from a series of mechanisms and cascades that, over time, drive progressive pathology.

I suggest that the aging process can be resolved into a series of distinct states (Figure B-1). Let us assume that under the arbitrary age of 120 it is

FIGURE B-1 Model for distinct phases in brain aging. It is becoming increasingly clear that at a mechanistic level, the primary driving mechanisms leading to progressive loss are multiphasic. The implication is that different therapeutic strategies will be needed at different phases of the processes.



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