Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model

Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a transgenic model. Aged APPswe/PS1ΔE9 mice were treated with saracatinib or memantine for 4 weeks and spatial memory improved to control levels. After drug washout, there was sustained rescue of both memory function and synapse density by saracatinib, but a loss of benefit from memantine. These data demonstrate a disease-modifying persistent benefit for saracatinib in a preclinincal Alzheimer's model, and distinguish its action from that of memantine. •Disease-modifying effects of saracatinib or memantine were assessed in vivo.•Saracatinib but not memantine exhibited persistent rescue of synapses and memory.•Saracatinib benefit was observed at least one month after therapy discontinuation.•Withdrawal study design can differentiate disease-modifying and symptomatic agents.