The Morphologic and Neurochemical Basis of Dementia: Aging, Hierarchical Patterns of Lesion Distribution and Vulnerable Neuronal Phenotype

Alzheimer's disease is the most common form of dementia in elderly individuals. Approximately 11% of the population older than 65, and up to 50% of individuals over 85 qualify as having “probable Alzheimer's disease” on the basis of clinical evaluation. Since the early description of the clinical symptoms and neuropathologic features of Alzheimer's disease, there has been an extraordinary growth in the knowledge of the morphologic and molecular characteristics of Alzheimer's disease. Although the pathogenetic events that lead to dementia are not yet fully understood, several hypotheses regarding the formation of the hallmark pathologic structures of Alzheimer's disease have been proposed. In this context, the use of specific histochemical techniques in the primate brain has greatly expanded our understanding of neuron typology, connectivity and circuit distribution in relation to neurochemical identity. In this respect, very specific subsets of cortical neurons and cortical afferents can be identified by their particular content of certain neurotransmitters and structural proteins. In this article, we discuss the possible relationships between the distribution of pathologic changes in aging, Alzheimer's disease, and possibly related dementing conditions, in the context of the specific elements of the cortical circuitry that are affected by these alterations. Also, evidence for links between the neurochemical phenotype of a given neuron and its relative vulnerability or resistance to the degenerative process are presented in order to correlate the distribution of cellular pathologic changes, neurochemical characteristics related to vulnerability, and affected cortical circuits.