Differential vulnerability, connectivity, and cell typology

The distribution of pathologic profiles and cell loss suggest that the cells of origin of certain parahippocampal projections and cortico-cortical circuits in neocortex are devastated in Alzheimer's disease (AD), whereas many other elements of cortical circuitry are resistant to degeneration. The loss of these cells and circuits leads to the effective disconnection and isolation of the regional components of complex distributed systems that subserve memory and cognition and, as such, represents the primary anatomic substrate for the dementia seen in AD. Such patterns of selective vulnerability in the neocortex offer important clues as to which cortical circuits are compromised in a given disease, but our ability to relate such patterns to potential cellular or molecular pathogenetic mechanisms is greatly hampered by our lack of data correlating the biochemical and morphological phenotype of neurons with connectivity in the human and nonhuman primate neocortex. De Lacoste and White have developed an excellent review of the literature concerning the notion of corticocortical disconnection as the key anatomic substrate for dementia in AD and, in addition, have included specific hypotheses that will aid in the further conceptualization and testing of this model (3). Also, they have succeeded in placing the available neuropathologic data on the distribution of neurofibrillary tangles (NFT), neuritic plaques (NP), and cell loss within the context of principles of neocortical and hippocampal connectivity that have emerged from experimental analyses of nonhuman primate cortex, a link that is essential in the development of the corticocortical disconnection hypothesis of AD (6,9, l 0,13,17,22,). Throughout their comprehensive and timely review, de Lacoste and White (3) refer to a disconnection/connectivity model of AD rather than a disconnection model. This is a crucial distinction, because it extends the basic observation that numerous corticocortical disconnections are likely to have occurred in AD and are causally related to dementia, to a hypothesis that deals directly with a mechanism for corticocortical disconnection. Although the connectivity half of the model is appealing from the perspective of pathogenesis, it is not an essential path to disconnection. Characteristics of these corticocortically projecting neurons other than their connectivity may also contribute to their demise. While I strongly support the statement by de Lacoste and White (3) that "more rigorous studies are required on the laminar and regional distribution of NFT in a series of sequentially interconnected architectural areas in cases with available neuropsychological profile," I believe that the question posed in their concluding section is equally important, and perhaps, more compelling: " . . . The perplexing question is why the neurons giving rise to long corticocortical connections are selectively involved in AD?" This latter question deals directly with the issue of selective vulnerability. Although much is known about the topographic organization of many corticocortical projections in monkey brain, little is known of their precise anatomic organization in human and few data are available that link connectivity to potential cellular and molecular specializations of these neurons in monkey or human cortex. It has been proposed that the vulnerability of certain corticocortical systems in AD is largely a reflection of their convergent input to the medial cortex (17,24). Within this scheme, the pathologic process is initiated in the medial temporal lobe (amygdala and/or hippocampal areas) and spreads transynaptically through the corticocortical projections. In fact, it has been proposed that a putative pathogen such as a virus or an environmental toxin might enter the brain through the olfactory system and thereby gain access to the structures of the medial temporal lobe (i.e., hippocampus and/or amygdala), and then spread to the association cortices of the frontal, temporal, and parietal lobes that are synaptically connected to this area (17,24). This hypothesized transneurohal spread suggests that certain neocortical association areas are particularly devastated in AD because they may be synaptically closer to the initial site of pathology than are the primary sensory areas. A spread of pathology along corticocortical pathways also may result from the loss of key growth factors or simply retrograde degeneration due to the loss of target neurons. The connectivity component of the disconnection/connectivity hypothesis has merit as a model for pathogenesis, however, it is equally feasible that the biochemical and morphologic phenotypes of the pyramidal neurons furnishing long corticocortical projections may predispose them to degeneration and/or NFT formation through a mechanism other than