In summary, our intriguing in vitro and in vivo findings strongly indicated that an adiponectin-mimetic novel nonapeptide crossed the BBB and had a good safety and protection profile, regulated neuronal metabolism-associated AdipoR1/AMPK targets, prevented neuronal insulin resistance, enhanced downstream insulin signaling, and consequently improved synaptic plasticity and memory functions in AD and Adipo−/− mice. This evidence concerns the gene ADIPOQ and Alzheimer disease.