In theory, the microanatomy of the hippocampal formation may provide an answer to both questions. The hippocampal formation is a complex structure made up of separate but interconnected subregions (Amaral and Witter, 1989): the entorhinal cortex, the dentate gyrus, the CA1 and CA3 subfields, and the subiculum (Figure 12.1). Because the subregions are connected in a unidirectional manner, the hippocampal formation functions as a circuit. Thus, a lesion in any individual hippocampal subregion will equivalently interrupt the circuit, leading to overlapping memory deficits.
Importantly, each hippocampal subregion houses a distinct population of neurons, unique in their molecular expression profiles (Zhao, Lein et al., 2001). It is this molecular uniqueness that accounts for why each hippocampal subregion is differentially vulnerable to mechanisms of dysfunction (Small, 2001). So, for example, transient hypoxemia causes memory deficits by targeting the CA1 subfield because of high expression of glutamate receptors in CA1 neurons, while, in contrast, an adrenalectomy causes overlapping memory deficits by targeting the dentate gyrus because neurons in this subregion express relatively high concentrations of corticosteroid receptors.
Based on this anatomical and molecular organization, the following hypothesis can be made: If AD and normal aging are indeed pathologically separate processes, then the odds are that they should targets different hippocampal subregions (Small, 2001). Establishing whether this anatomical dissociation exists, therefore, is an effective approach for answering the first question (Is age-related hippocampal dysfunction etiologically homogeneous?); and if it does exist, then this anatomical dissociation can potentially be used in dissociating one cause from the other.
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