The association between elevated plasma levels of homocysteine (Hcy) and nutritional status has been shown in Alzheimer disease (AD) patients and also in vascular dementia (VaD). Moreover, a previous study provided evidence that the relation between a high Hcy level and low vitamin B12 and folate levels in AD patients is due to biochemical damage, rather than a nutritional deficit. The purpose of this study was to investigate the relationship between plasma Hcy levels and vitamins involved in its metabolism in AD and VaD. Twenty-two VaD patients, 22 AD patients and 24 healthy subjects were studied for Hcy, vitamin B12, vitamin B6 and folate. All patients and control subjects were comparable for age, educational level, nutritional and socioeconomic status. None of them showed macrocytic anemia or impaired renal function. Hcy was significantly increased in VaD patients (26.0 +/- 6.58 micromol/l) as compared to controls (10.7 +/- 3.0 micromol/l) and AD patients (22.3 +/- 4.51 micromol/l; p<0.001); however, AD patients also showed increased levels of Hcy. Folates were significantly reduced in both VaD (10.8 +/- 2.81 nmol/l) and AD (10.0 +/- 2.72 nmol/l; p<0.001) patients, while vitamin B12 showed significantly reduced levels only in AD patients (392.1 +/- 65.32 pmol/l; p=0.02). Vitamin B6 was not significantly different in the three groups. Increased levels of Hcy associated with low vitamin B12 plasma levels were found only in AD patients. This observation led us to consider that vitamin B12 metabolism does not represent the direct consequence of the nutritional status and suggests that neuronal damage results in a functional vitamin B12 deficiency, as emphasized by recent reports. New therapeutic strategies are necessary, considering that available pharmaceutical forms of vitamin B12 are not utilized by neurons in oxidative stress conditions.