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Background: The concept that the neurotoxicity of amyloid β protein could partly result from vascular effects that may be detected in peripheral microcirculation is new. Methods: We compared peripheral endothelial vascular responses of patients with early clinically confirmed Alzheimer's disease (AD) to that of people with normal cognition and those with other forms of dementia. Acetylcholine (ACh) was iontophoresed into the skin and the resultant vasodilator response was measured using laser Doppler flowmetery. Results:The ratio of ACh response to saline (ratio E/S) was determined. Mean ± SEM of ratios E/S were 8.8 ± 0.9 for controls (n = 168), 1.4 ± 0.1 for AD patients (n = 80) and 3.1 ± 0.5 for other dementia (n = 84). Using the optimal cut-off point of E/S ratio of 1.9, an 80% diagnostic sensitivity and specificity for AD have been observed. When the control sample was filtered for those with cardiovascular diseases and with MMSE < 28, this improved the specificity to 90% (n = 119). Furthermore, 15 subjects were randomly drawn from a longitudinal healthy ageing study. Five of those subjects met the criteria for mild cognitive impairment (MCI) after eight years of follow up using a battery of cognitive tests. When tested for their E/S ratio in a blind fashion, the skin test successfully identified those subjects. Conclusions: The results support our hypothesis that endothelial alterations can be detected early in the course of the disease. We suggest that this simple skin test could potentially be applied as diagnostic adjunct in patients with mild cognitive symptoms or those with early clinical evidence of AD.