The goal of this study was to evaluate the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD+-dependent HDACs, in 3xTg mice. Data found that oral nicotinamide treatment restored cognitive deficits that manifest in the 3xTg-AD mice, while improving short-term spatial memory in non-demented control animals. However, nicotinamide treatment had no significant effects on beta amyloid load or, beta amyloid peptide production. Tau pathology is decreased following nicotinamide treatment, and drug treatment was found to selectively reduce a phosphorylated species of tau ( phosphoThr231-tau) associated with microtubule depolymerization and implicated in AD. Nicotinamide had no effect on the levels of cyclin-dependent kinase 5 (cdk5) and GSK3β but did up regulate p25 which is linked to improved learning and memory. In addition, treatment inhibited brain sirtuins, increased acetylated -tau,upregulated proteins associated with increased microtubule stabilization such as SirT2, and MAP2c and reduced ubiquninated tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.