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By interrogating the functional integrity of the hippocampal circuit in humans and animals, a double anatomical dissociation has emerged distinguishing early AD from normal aging. During its earliest stages, AD targets the entorhinal cortex and spares the dentate gyrus, while, in contrast, normal aging spares the entorhinal cortex but targets the dentate gyrus (Figure 12.3).

This anatomical profiling has three important implications. First, the anatomical dissociation establishes that AD and normal aging are pathogenically separate processes, forevermore putting an end to the possibility that age-related memory decline might solely represent AD. Second, the anatomical dissociation, and the ability to visualize this dissociation in living subjects, can be exploited as a diagnostic tool. Although we currently do not have effective treatments for AD, on theoretical

Figure 12.3. A double-anatomical dissociation distinguishes early Alzheimer's disease from normal aging. Alzheimer's disease targets the neurons of the entorhinal cortex with relative sparing of the neurons of the dentate gyrus. In contrast, normal aging targets the neurons of the dentate gyrus with relative sparing of the neurons of the entorhinal cortex. This dissociation establishes that Alzheimer's disease and normal aging are separate processes, and that both contribute to age-related hippocampal dysfunction. Furthermore, this dissociation, and the ability to visualize dysfunction in individual hippocampal subregions in living subjects, provide a method for distinguishing the early stages of Alzheimer's disease from normal age-related hippocampal dysfunction. Finally, this dissociation sets the stage for uncovering the molecular underpinnings of both Alzheimer's disease and normal age-related memory decline.

Figure 12.3. A double-anatomical dissociation distinguishes early Alzheimer's disease from normal aging. Alzheimer's disease targets the neurons of the entorhinal cortex with relative sparing of the neurons of the dentate gyrus. In contrast, normal aging targets the neurons of the dentate gyrus with relative sparing of the neurons of the entorhinal cortex. This dissociation establishes that Alzheimer's disease and normal aging are separate processes, and that both contribute to age-related hippocampal dysfunction. Furthermore, this dissociation, and the ability to visualize dysfunction in individual hippocampal subregions in living subjects, provide a method for distinguishing the early stages of Alzheimer's disease from normal age-related hippocampal dysfunction. Finally, this dissociation sets the stage for uncovering the molecular underpinnings of both Alzheimer's disease and normal age-related memory decline.

grounds arresting or even reversing the cell-sickness stage of AD is more likely than treating the cell-death stage of AD. Currently, relying on cognitive measures alone, we cannot accurately diagnose AD during its early cell-sickness stage because it cognitively overlaps with normal aging. Imaging techniques that can assess the functional integrity of the hippocampal subregions—in particular, the entorhinal cortex and the dentate gyrus—are well suited to achieve this diagnostic goal. Testing the diagnostic capabilities of any technique requires large-scale, epidemiologically rigorous, prospective studies. One such study is currently underway, testing whether the imaging approaches discussed in this chapter can be used to diagnose AD during its earliest stages.

Finally, pinpointing the hippocampal neurons most vulnerable to AD and to aging is a required first step for uncovering the molecular causes of each process. By isolating the molecular defects that underlie the rare autosomal-dominant form of AD, and by expressing these molecules in cell culture and in transgenic mice, tremendous strides have been made uncovering the molecular biology of AD. Nevertheless, the primary molecules whose defects underlie autosomal-dominant AD are normal in sporadic AD, the common form that accounts for over 95% of all cases. Thus, the primary molecular defects of the vast majority of AD remain unknown. Pinpointing the entorhinal cortex as the site of greatest vulnerability provides an anatomical handle with which to tackle this problem. Specifically, comparing the molecular profiles of the entorhinal cortex of affected and unaffected brains, at the mRNA or protein level, holds great promise for uncovering heretofore unidentified pathogenic molecules underlying sporadic AD. In a similar fashion, mapping age-related changes in the molecular profiles of the dentate gyrus, among healthy brains, may lead to insights into the molecular causes of memory decline associated with normal aging.

Age-related hippocampal dysfunction has emerged as a serious societal problem. As life expectancy is expanding, most of us do not simply want to live longer, but rather we would like to age with cognitive grace, remaining intellectually engaged in our information-rich environments. As discussed in this chapter, and in accordance with fundamental principles of clinical neuroscience, pinpointing the population of neurons differentially vulnerable to aging and to AD is an important first step towards developing effective diagnostics and, one day, even ameliorating the age-related slide into forgetfulness.

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How To Add Ten Years To Your Life

How To Add Ten Years To Your Life

When over eighty years of age, the poet Bryant said that he had added more than ten years to his life by taking a simple exercise while dressing in the morning. Those who knew Bryant and the facts of his life never doubted the truth of this statement.

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