It has been generally hypothesized that increase in some neurotoxicity causes Alzheimer's disease (AD). However, it is also possible that decrease in defending ability that intrinsically prevents the AD-linked neurotoxicity contributes to the AD pathogenesis. Humanin was originally discovered as a putative defending molecule that inhibits neuronal cell death and dysfunction related to AD and innumerable studies have suggested that Humanin exhibit anti-AD activities. However, because the potency of Humanin is too weak (IC50 of Humanin is 10 μM) and the gene encoding Humanin is unable to be determined, the significance of Humanin in the AD pathogenesis remains in question. Secreted calmodulin-like skin protein (CLSP) inhibits neuronal cell death and dysfunction related to AD by binding the heterotrimeric Humanin receptor. Based on facts that the inhibitory activity of CLSP is far stronger than Humanin (IC50 of CLSP is 0.1 nM whereas that of Humanin is 10 μM) and sufficient concentrations of CLSP are present in the cerebrospinal fluid and blood, CLSP is regarded to be the physiological agonist of the heterotrimeric Humanin receptor. In addition, we preliminarily found that the levels of CLSP in the cerebrospinal fluid (CSF) are likely lower in persons with the ApoE4 gene than those with non-ApoE4 genes and discovered a putative specific inhibitor of CLSP. This study will be performed to establish the significance of anti-AD therapy that potentiates the CLSP-mediated AD-defending signal and develop a biochemical diagnostic method of AD by measuring the levels of CLSP and its inhibitor 14-3-3sigma in the clinical samples.