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Mild cognitive impairment (MCI) is a syndrome defined as cognitive decline, but not sufficient to meet the criteria for any specific dementia. Although subjects with MCI may have an increased risk to develop AD, this clinical state encompasses several subtypes of cognitive dysfunction of different etiologies, none of which necessarily progresses to AD. The current inability of clinical criteria to accurately identify this at-risk group for AD development is fuelling the interest in biomarkers able to supplement clinical approaches. We recently described a blood-based cytofluorimetric method for conformationally altered p53 protein detection that allows the discrimination of AD patients from control subjects and patients affected by other dementias. The same protein also predicted progression to AD in preclinical patients with MCI two years before clinical diagnosis of AD was made. Herein, we describe these findings and discuss the potential of the test in diagnosing AD.

Background: Alzheimer’s disease (AD) cannot be diagnosed until dementia appears, thus the detection of early disease-related biomarkers is crucial to facilitate the development of new diagnostic tools and drug therapies. Candidate biochemical markers for AD should be molecules representing some of the cerebral pathogenetic processes typical of AD. Alternatively they should represent altered metabolic or cellular processes in the brain or in peripheral tissues from affected patients. In research of secondary markers we recently found an intriguing correlation between p53 and AD. In particular, we demonstrated that fibroblasts from sporadic AD patients specifically express an unfolded and detectable conformational state of p53 that allows to differentiate them from fibroblasts of age-matched non-AD subjects (Uberti et al., 2006). Methods: In this study, we used a rapid and easy flow-cytometric approach to investigate the different expression of conformationally altered p53 between AD and non-AD subjects on peripheral blood cells, which represent a more accessible cellular model than fibroblasts. We enrolled more than 150 subjects and tested the content of unfolded p53 in AD, non AD and subjects affected by other dementia. Results: We found that peripheral blood cells from AD specifically expressed increased levels of unfolded p53 in comparison with non AD subjects. A statistically significant correlation was observed when the expression of unfolded p53 and the age of both control subjects and AD patients were considered thus demonstrating that altered p53 is an age-dependent factor. In order to evaluate the diagnostic performance of unfolded p53 as an AD trait marker, we calculated sensitivity and specificity within different age intervals and we found that these values were more significant in subjects up to 70 years of age compared to the values in individuals older than 70 years. Within this specific age interval (< 70 years), sensitivity and specificity were respe