Chapter 28 The systems-level organization of cholinergic innervation in the human cerebral cortex and its alterations in Alzheimer's disease

Abstract

The cholinergic innervation of the cerebral cortex has now become one of the most dynamic areas of research and offers exciting opportunities for exploring the chemical neuroanatomy of cognition, age-related memory impairments, and Alzheimer's disease. The cholinergic pathway from the basal forebrain is the most massive of all extra-thalamic corticofugal projections of the cerebral cortex. Developments based on electron microscopy, immunocytochemistry, antibodies to recombinant receptor subtypes, in situ hybridization, single unit recordings, and selective immunotoxic lesioning have introduced a wealth of new information on the organization and function of this pathway in various animal species, including humans. The cholinergic pathway emanating from the basal forebrain constitutes one of the most important modulatory afferents of the mammalian cortex. The initial expectation that the cholinergic deficiency would provide a unifying pathophysiological basis for Alzheimer's disease and that cholinergic therapies would cure the dementia are clearly too optimistic. Nonetheless, the cortical cholinergic denervation remains one of the earliest, most severe, and most consistent transmitter changes in this disease. The cholinergic depletion may provide an important substrate for the neuropsychological features of Alzheimer's disease and may eventually yield important clues to its pathogenesis.