Klotho (KL) is a single-pass transmembrane protein encoded by the anti-aging gene KL and a circulating factor that plays a key role in cellular metabolism and homeostasis. KL pretreatment of neurons can reduce neuronal injury induced by toxic amyloid-β and glutamate, a process that is central to the pathogenesis of Alzheimer’s disease (AD), which indicates that KL plays a neuroprotective role in AD progression. Recent studies have shown that KL level is significantly decreased in the cerebrospinal fluid of AD patients. Meanwhile, KL overexpression significantly improves the cognition of AD model mice and this outcome is independent of its anti-aging effect. Given that KL is closely associated with AD pathogenesis, upregulation of KL levels in the early stages of AD may present as a therapeutic strategy to prevent further deterioration and to ameliorate the outcome of AD patients.