As commonly experienced, and as neuropsychologically documented, our cognitive abilities decline with advancing aging (Zelinski and Burnight, 1997). Luckily for us, age-related cognitive decline is not diffuse, but rather aging targets select cognitive domains. The ability to consciously memorize new and complex experiences—for example, learning the name of a new acquaintance—is one cognitive domain particularly sensitive to the aging process (Small, Stern et al., 1999). This cognitive ability requires the hippocampal formation (Amaral and Witter, 1989), a brain structure nestled deep in the temporal lobes (Figure 12.1).
As clinicians, we are interested in the etiology of age-related hippocampal dysfunction. One cause is undoubtedly Alzheimer's disease (AD), a gradually progressive disorder that typically manifests in later life. Anatomically, AD begins by targeting the hippocampal formation, presenting as mild forgetfulness, but ultimately sweeps throughout the neocortical mantle, devastating most cognitive abilities in its wake (Masur, Sliwinski et al., 1994; Jacobs, Sano et al., 1995) and leading to dementia. Within each affected area, AD progressed through different pathophysiological stages. Early on, AD causes neurons to malfunction (Selkoe, 2002), manifesting as metabolic and synaptic failure, before causing neurons to die. Accordingly, a distinction is sometimes made between the early ''cell sickness'' stage versus the later ''cell death'' stage of AD (Small, 2005).
Not every aging individual with age-related hippo-campal dysfunction progresses to AD dementia, raising the possibility that the aging process itself might affect hippocampal function. A wide range of nonhuman studies support this possibility (Barnes, 1994; Gallagher and Rapp, 1997; Erickson and Barnes, 2003). All aging nonhuman mammals manifest hippocampal dysfunction, yet no species besides our own develops AD. Thus, all species develop non-AD age-related memory decline, and it would seem unlikely that humans would be spared this species-wide process. Nevertheless, the possibility still exists that in humans age-related hippocampal dysfunction uniformly reflects the early stages of AD, and that if humans live long enough all will develop full-fledged AD.
This chapter will review a combination of human and animal studies that have set out to address two interrelated questions: First, is age-related hippocampal dysfunction etiologically homogeneous—uniformly reflecting the early stages of AD—or is age-related hippo-campal caused by both AD and by normal aging? Second, if age-related hippocampal dysfunction is caused by both AD and normal aging, how can they be distinguished from each other?
Figure 12.1. The functional organization of the hippocampal formation. The hippocampal formation is a cylindrical structure located in the medial temporal lobes (demarcated in the upper panel). The microanatomy of the hippocampal formation (bottom panel) is best appreciated by viewing a transverse slice through the body of the hippocampal formation (stippled line in the upper panel). The hippocampal formation is made up of the anatomically and molecularly distinct subregions—the entorhinal cortex (EC), the dentate gyrus (DG) and the CA1 and CA3 subfields (bottom panel). The hippocampal subregions are interconnected, giving rise to the hippocampal circuit. The circuit organization of the hippocampal formation accounts for why dysfunction in any individual hippocampal subregion will equivalently interrupt the circuit, causing overlapping memory deficits. The molecular organization of the hippocampal formation accounts for why each hippocampal subregion is differentially vulnerable to mechanisms of dysfunction.
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