Klotho, encoded by the KL gene, is a single-pass transmembrane protein and a circulating factor that plays a key role in cellular metabolism and body homeostasis and has been associated with age-related diseases. Alterations of this protein seem to influence the development of serotonergic neurons and could play a role in major depression in the elderly. Pretreatment of neurons with Klotho protein can avoid neuronal injury related to the toxic amyloid-β and glutamate, centrally related to the pathogenesis of Alzheimer's disease (AD), in order that Klotho protein could play a neuroprotective role in AD patients. Late-life depression, mild cognitive impairment, and dementia are different nosological entities but share common neurobiological facets and could represent a clinical continuum. Enhancement of Klotho levels in the early stages of the disease could represent a therapeutic strategy to prevent further deterioration and to ameliorate the outcome of elderly AD patients with or without major depression.