An esterase, paraoxonase 1 (PON1), protects against organophosphate neurotoxicity and decreases lipoprotein oxidation. Two polymorphisms of PON1 [192 (R or Q) and 55 (M or L)] exist and are associated with coronary artery disease. We have previously shown that serum PON1 activity (PON1a) is lower in vascular dementia (VaD) than in Alzheimer's disease (AD), suggesting that PON1a may distinguish VaD from AD. As PON1 polymorphism modifies PON1a, we determined 192 and 55 PON1 polymorphisms by sequence-specific primer PCR in 64 healthy subjects (HS; mean age: 79.5 +/- 6.3 years; 38 women) and in 72 patients (mean age: 80.2 +/- 6.8 years; 51 women) undergoing cognitive evaluations. According to DSM-IV/NINCDS/ADRDA/NINDS/AIREN criteria, 45 patients (mean age: 80.0 +/- 7.2 years, 34 women) had AD and 27 patients (mean age: 79.8 +/- 6.6 years, 16 women) had VaD. We also measured serum PON1a by spectrophotometry. No significant differences in phenotype distributions among the three study groups were detected by chi(2) test. Among the variables, age, sex, and phenotypes 192 and 55, logistic regression selected only polymorphism 192, but not 55, as a discriminating factor between AD and VaD (p < 0.05). Substitution of serum PON1a for genotype yielded a similar result. PON1 polymorphism 192 appears to be a reliable marker to distinguish patients with AD from patients with VaD and from healthy subjects. Changes in 192 polymorphism distributions in AD and in VaD may at least partially explain the significant difference in PON1a in these two types of dementia.