We have previously shown that the incubation of PC12 pheochromocytoma cells with beta-amyloid for 24 hours causes a significant increase in the choline conductance of the cells. If a similar effect occurs in cholinergic neurons of patients with Alzheimer's disease (AD), the leakage of choline out of the neurons would decrease synthesis and secretion of acetylcholine. This scenario has two important implications. First, the decreased secretion could explain the decreased concentration of acetylcholine found in the brains of AD patients. Second, in view of recent evidence that a decrease in acetylcholine concentration causes an increase in beta-amyloid production, there would be positive feedback between decreased acetylcholine concentration and increased beta-amyloid concentration. We have developed a mathematical model that includes this positive feedback. According to the model, acetylcholine concentration declines with age in a manner that is very sensitive to the rate of production of beta-amyloid. For example, a 10% increase in the rate of beta-amyloid production can lower the age of onset of AD, modeled as the age at which the acetylcholine concentration declines to half of its initial value, from 110 years to 60 years. This sensitivity could explain the wide variability of the age of onset of sporadic AD.
