Elevated level of osteoprotegerin (OPG), a pleiotropic cytokine involved in bone metabolism, has been associated with coronary heart disease and higher cardiovascular mortality. Because cardiovascular disorders are recognized risk factors for dementia, the study of OPG as a disease marker in vascular dementia (VaD) and Alzheimer's disease (AD) seemed worthy of investigation. OPG concentration was determined by ELISA in an Italian cohort consisting of 39 VaD patients, 36 AD patients, and 39 non-demented controls strictly matched for age and gender. Plasma OPG levels were positively related to age in both demented and non-demented persons. OPG concentrations were significantly higher in both VaD (median: 4.75 pmol/l; interquartile range: 3.42-6.85 pmol/l; P<0.0001) and AD (median: 4.02 pmol/l; interquartile range: 3.07-4.77 pmol/l; P=0.0278) compared to non-demented controls (median: 3.24 pmol/l, interquartile range: 2.70-3.98 pmol/l). After allowance for confounding factors (age, gender and APOE ε4 allele), plasma OPG levels remained independently associated with the presence of VaD (OR = 2.51; 95% CI 1.46-4.32; P=0.0009) and AD (OR = 2.17; 95% CI 1.18-3.99; P=0.0126). Our study demonstrates that OPG may be regarded as a novel biomarker of dementia in the Italian population. These results further support the hypothesis that vascular factors may not only play a role in the pathogenesis of VaD but also in the pathogenesis of AD.

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