The distribution of peripheral T cell subsets in young and healthy old people is markedly different, characterized by decreased numbers of naïve cells and increased numbers and clonal expansions of memory cells, predominantly in the CD8+ MHC class I-restricted subset. Here, however, we document dramatic alterations in naïve and memory subsets of CD4+ cells in patients with mild Alzheimer's disease (AD), with greatly decreased percentages of naïve cells, elevated memory cells, and increased proportions of CD4+ but not CD8+ cells lacking the important costimulatory receptor CD28. CD4+CD25(high) potentially T regulatory cells with a naïve phenotype are also reduced in AD patients. Together these data provide stronger evidence than hitherto presented for more highly differentiated CD4+ as well as CD8+ T cells in AD patients, consistent with an adaptive immune system undergoing persistent antigenic challenge and possibly manifesting dysregulation as a result.