Calmodulin-like skin protein (CLSP), a secreted peptide, inhibits neuronal death in cell-based Alzheimer’s disease (AD) models and transgenic overexpression of the CLSP gene suppresses synaptic loss and memory impairment in AD model mice, APPswe/PS1dE7 double transgenic mice (APP/PS1 mice). We previously showed that adiponectin, a CLSP potentiator/protector, dominantly determined the CLSP activity in the central nervous system where there are sufficient concentrations of CLSP, higher concentrations of CLSP inhibitors such as apolipoprotein E, and smaller concentrations of adiponectin. We also found that both the levels of brain adiponectin and the intraneuronal levels of SH3BP5, an important effector of the CLSP signal, were reduced in both AD patients and APP/PS1 mice. In this study, the restoration of the CLSP activity by subcutaneous injection of a hybrid peptide named CLSPCOL consisting of CLSP(1-61) and the collagen-homologous region of adiponectin, which has more potent neuroprotective activity than CLSP, is insensitive to the suppression by the CLSP inhibitors, and is efficiently recruited into brains, alleviates dementia and hippocampal synaptic loss in the aged APP/PS1 mice. Collectively, these results suggest that the reduction in the CLSP activity leads to the insufficient protection of neurons from neurotoxicity in the AD brains and the restoration of the CLSP activity is a promising strategy for the treatment of AD.