Overall, our data, obtained in a non-Tg model of AD, indicate that a deficit in TGF-β1 might represent one of the neurobiological links between depression and AD and also that rescue of TGF-β1 signaling with second-generation antidepressants might represent a new pharmacological strategy to prevent both amyloid-induced depression and cognitive decline in AD. The gene discussed is TGFB1; the disease is major depressive disorder.