Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer's disease.

Vascular risk factors increase the risk of developing Alzheimer's disease. Increased concentrations of circulating homocysteine are associated with an increased risk of both vascular disease and Alzheimer's disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. There is an increase in the concentration of ADMA in the circulation in vascular disease. We measured the concentrations of homocysteine, ADMA and nitric oxide (as nitrate and nitrite) in the plasma of 25 patients with Alzheimer's disease and 25 control subjects. There was a highly significant increase in the plasma concentration of homocysteine (P<0.001) and ADMA (P<0.0001) and a highly significant decrease in the plasma concentration of nitric oxide (P<0.0001) among the Alzheimer's patients. In the combined patient and control groups a highly significant positive correlation was found between the plasma concentrations of homocysteine and ADMA (r=0.782, P<0.0001). In addition, significant negative correlations were detected between the plasma concentration of nitric oxide and the plasma concentration of homocysteine (r=-0.592, P<0.0001) and ADMA (r=-0.789, P<0.0001). These significant correlations were found to persist, even when they were restricted to the Alzheimer's patients. The inhibition of endothelial nitric oxide synthesis by ADMA impairs cerebral blood flow, which may contribute to the development of Alzheimer's disease. Endothelial dysfunction is also associated with atherosclerosis and stroke, which are important risk factors for Alzheimer's disease. Inflammation plays an important role in Alzheimer's disease and the inhibition of endothelial nitric oxide by ADMA may increase the concentration of inflammatory mediators in the brain. The inhibition of neuronal nitric oxide synthesis by ADMA may cause cognitive dysfunction in Alzheimer's disease.