Despite increased neurogenic differentiation markers in the hippocampal CA1 in Alzheimer’s disease (AD), neurons are not replaced in CA1 and the neocortex in the disease. ß-amyloid (Aß) might cause deterioration of the brain microenvironment supporting neurogenesis and the survival of immature neurons. To test this possibility, we examined whether Aß alters the expression of cell fate determinants in cerebral cortical cultures and in an AD mouse model (PrP-APPSW). Up-regulation of Mash1 and down-regulation of Olig2 were found in cerebral cortical cultures treated with Aß1-42. Mash1 was expressed in nestin-positive immature cells. The majority of Mash1-positive cells in the cortical culture co-expressed Olig2. Aß increased the proportion of Olig2-negative/ Mash1-positive cells, which did not express cell-specific markers of neurons, astrocytes or oligodendrocytes, indicating that Aß1-42 may alter the expression of Mash1 and Olig2 in immature cells, possibly neural stem/progenitor cells. A decrease in Olig2+ cells was also observed in the cerebral cortex of adult PrP-APPSW mice. Cotransfection experiments with Mash1 cDNA and Olig2 siRNA revealed that overexpression of Mash1 in neurosphere cells retaining Olig2 expression enhanced neural differentiation, but accelerated death of Olig2-depleted cells. Growth factor deprivation, which down-regulated Olig2, accelerated death of Mash1-overexpressing neurosphere cells. We conclude that cooperation between Mash1 and Olig2 is necessary for neural stem/progenitor cells to develop into fully mature neurons and that down-regulation of Olig2 by Aß in Mash1-overexpressing cells switches the cell fate to death. Maintaining Olig2 expression in differentiating cells by administering EGF and FGF2 could have therapeutic potential.