Neurons in the brains of those with Alzheimer’s disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization, axonal integrity and neuronal dysfunction. One therapeutic hypothesis posits that MT-stabilizing drugs such as the anti-cancer drug epothilone D (EpoD). In this study the authors demonstrate that EpoD is brain-penetrant and that EpoD treatment of 3-month-old male PS19 mice, for a 3 month period, significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.