BACKGROUND The incidence of dementia increases exponentially with age but knowledge of real disease-modifying interventions is still limited. OBJECTIVES To describe the study design and methods of a large prospective cohort study aimed at exploring the complex underlying relationships existing among cognition, frailty, and health-related events in older persons with cognitive impairment. DESIGN Prospective cohort study of a representative population of outpatients attending the Treviso Cognitive Impairment Center between 2000 and 2010. SETTING The TREVISO DEMENTIA (TREDEM) Study conducted in Treviso, Italy. PARTICIPANTS 490 men and 874 women, mean age 79.1 ± 7.8 years (range 40.2-100 years). MEASUREMENTS Physiological data, biochemical parameters, clinical conditions, neuroradiological parameters (e.g., brain atrophy and cerebral vascular lesions identified by computerized tomography scans), neuropsychological assessment, and physical function markers were measured at baseline. Patients were followed-up to 10 years. RESULTS The final sample included in the study was predominantly composed of women and characterized by an initial physical function impairment and increased vascular risk profile. Cognitive function of the sample population showed moderate cognitive impairment (Mini Mental State Examination 20.2 ± 6.3; Clinical Dementia Rating 1.2 ± 0.7), and a prevalence of vascular dementia of 26.9%. Cortical, subcortical and hippocampus atrophy were all significantly correlated with age and cognitive function. CONCLUSION Results obtained from the preliminary analyses conducted in the TREDEM study suggest that the database will support the accomplishment of important goals in understanding the nature of cognitive frailty and neurodegenerative diseases.