The recognition that G(1)/S checkpoint dysfunctions in Alzheimer's disease (AD) has opened a novel avenue for better understanding the pathogenesis of AD, as well as for searching for new biomarkers for early diagnosis of AD. In present study, we investigated Cyclin E, Rb, CDK2 and E2F-1, four G1/S checkpoint proteins, in the lymphocytes from AD and non-AD individuals, and explored their potential for diagnosis application. A total of 176 age-matched subjects were enrolled, including 74 AD patients, 80 cognitively normal individuals, 11 patients with Parkinson's disease (PD) and 11 patients with vascular dementia (VaD). Peripheral blood lymphocytes were collected from each individual, and Cyclin E, Rb, CDK2, E2F-1 were analyzed by enzyme-linked immunosorbent assay, western blot, confocal microscopy and flow cytometry. The results showed that four proteins increased in AD compared with other three groups (P < 0.05), with CDK2 and E2F-1 showing higher statistical significance (P < 0.01). Their specificity/sensitivity (Cyclin E 84%/81%; Rb 74%/89%, CDK2 80%/78%, E2F-1 85%/85%) were acceptable, suggesting their potential as biomarkers for AD. Furthermore, these four proteins had the best sensitivity/specificity and highest Area Under the Curve (AUC) in mild-moderate AD compared with the severe AD. (C) 2012 Elsevier Ireland Ltd. All rights reserved.