Regulatory T lymphocytes (Treg) play a fundamental importance in modulating the relative balance between inflammation and immune tolerance, and alterations of these cells are observed in inflammatory diseases. To better characterize the neuroinflammatory processes suggested to be associated with Alzheimer's disease (AD) and to clarify the possible role of Treg cells in this process, we extensively analyzed these cells (CD4 + CD25highFoxp3+) in patients with either severe AD (n=25) or mild cognitive impairment (MCI) (n=25), comparing the results with those of two groups of healthy controls (HC) (n=55). Because the intra- or extracellular expression of programmed death receptor 1 (PD1) identifies functionally diverse subsets of Treg we also analyzed such subpopulations. Results showed that, whereas both Treg and PD1pos Treg are increased in MCI and AD patients compared to HC, PD1neg Treg, the subpopulation of Treg cells endowed with the strongest suppressive ability, are significantly augmented in MCI patients alone. In these patients amyloid-β-stimulated-T cells proliferation was reduced and Treg-mediated suppression was more efficient compared to both AD and HC. The observation that PD1neg Treg, cells are increased in MCI patients reinforces the inflammatory origin of AD and supports a possible beneficial role of these cells in MCI that is lost in patients with full-blown AD.