Abstract: Classical inhibitors of PDE4 lack subtype selectivity due to exact amino acid sequence conservation of the catalytic site，and consequently，development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors （i.e.，for PDE4A，B，or D） could overcome this issue，conservation of the catalytic region，to which classical inhibitors bind，limits this approach. The present study examined the effects of BPN14770，an allosteric inhibitor of PDE4D，which binds to a primate-specific，N-terminal region，conferring greater than 260-fold selectivity for PDE4D. BPN14770 was 100- fold more potent for improving memory and cognition in humanized PDE4D （hPDE4D） mice，which expressed the primate-specific binding sequence，compared to wild-type mice；meanwhile，it exhibited low potency in a mouse surrogate model for emesis. The behavioral and matching neurochemical data presented established a relationship between PDE4D target engagement and effects on cognition for BPN14770. Furthermore，BPN14770 reversed memory and cognitive deficits induced by β-amyloid peptide 1-42 （Aβ42） in Morris water maze，Y maze and novel object recognition tests in the humanized PDE4D mice. The morphological analyses suggested that the number of dendrites and the dendritic length in the CA1 of hippocampus were significantly increased after the Aβ42-treated hPDE4D mice were administered of BPN14770 for two weeks. The neurochemical and molecular biological assays suggested that neuroplasticity-related proteins and neurotrophic factor BDNF in the hippocampus of hPDE4D mice were significantly increased after the hPDE4D mice were treated with BPN14770. These findings suggest clinical potential for PDE4D selective inhibitors in disorders with cognitive deficits such as Alzheimer’s disease，which affects approximately 20 million people worldwide and nearly 5 million people in the United States.