BACKGROUND: Elevated plasma total homocysteine (tHcy) concentrations are common in the elderly and have been suggested to be a risk factor for dementia. OBJECTIVE: In an elderly population, we examined the relation between plasma tHcy and scores on the Mini-Mental State Examination (MMSE), a commonly used screening measure of cognitive impairment in general practice. DESIGN: Fasting plasma tHcy concentrations were measured in 650 healthy, cognitively normal Italian community dwellers aged > or = 65 y (x +/- SD: 72.8 +/- 6.0 y). Socioeconomic status; serum folate, vitamin B-12, and creatinine; other potential dietary and lifestyle determinants of tHcy; and conventional vascular disease risk factors were also assessed. RESULTS: Subjects with MMSE scores of 26-28 had higher plasma tHcy concentrations (12.7 micromol/L; range: 12.2-13.2 micromol/L) than did those with scores > 28 (11.9 micromol/L; 11.4-12.3 micromol/L; P < 0.01). Subjects with scores of 24-25 had higher plasma tHcy concentrations (14.5 micro mol/L; 13.5-15.6 micromol/L) than did subjects with scores of 26-28 (P < 0.01) or > 28 (P < 0.001). The risk of hyperhomocysteinemia (plasma tHcy > 15 micromol/L) was higher in subjects with scores of 24-25 (odds ratio: 3.81; 95% CI: 1.9, 7.5) or 26-28 (odds ratio: 1.96; 95% CI: 1.3, 3.0) than in those with scores > 28. The results did not change after adjustment for conventional vascular risk factors and for age, medical, dietary, and lifestyle determinants of plasma tHcy. CONCLUSION: Elevated plasma tHcy has an independent, graded association with concurrent cognitive impairment as measured with the MMSE in healthy elderly community dwellers.