Cholinergic deficiency in Alzheimer's disease. Pathogenic model.

Genetic vulnerability factors are becoming more important in AD, yet only a minority of cases are familial, and of these only a portion are genetically determined. Because, early in the course, neurodegeneration is occurring in vulnerable cholinergically innervated regions and not throughout the brain as a whole, AD may be conceptualized as a corticolimbic system neurodegenerative disorder involving the entorhinal cortex, hippocampus, and amygdala. This conceptualization has obvious implications for the development of therapies since future interventions may be designed to prevent or slow neurodegeneration or improve clinical signs by modulating risk factors, beta-amyloid deposition, and phosphorylation of tau proteins; inhibiting inflammatory or oxidative processes; or enhancing cholinergic function in various ways. The recently reported effects of antioxidants, including vitamin E and selegiline, in prolonging time to institutionalization, death, or significant worsening, is one example of the feasibility of this approach, as are the observations that anti-inflammatory use may reduce AD risk and that long-term cholinesterase inhibitor use may delay nursing home placement. At present, approaches that are focused on neurotransmitter systems may prove more immediately accessible targets for therapeutic intervention.