The basal levels of extracellular Zn²⁺ are in the range of low nanomolar concentrations in the hippocampus and perhaps increase age-dependently. Extracellular Zn²⁺ dynamics is critical for cognitive activity and excess influx of extracellular Zn²⁺ into hippocampal neurons is a known cause of cognitive decline. The dentate gyrus is vulnerable to aging in the hippocampus and affected in the early stage of Alzheimer’s disease (AD). The reasons remain unclear. Neurogenesis-related apoptosis may induce non-specific neuronal depolarization by efflux of intracellular K⁺ in the dentate gyrus and be markedly increased along with aging. Extracellular Zn²⁺ influx into dentate granule cells via high K⁺-induced perforant pathway excitation leads to cognitive decline. Modified extracellular Zn²⁺ dynamics in the dentate gyrus of aged rats is linked with vulnerability to cognitive decline. Amyloid-β_1–42 (Aβ_1–42) is a causative candidate for AD pathogenesis. When Aβ_1–42 concentration reaches picomolar in the extracellular compartment in the dentate gyrus, Zn–Aβ_1–42 is formed in the extracellular compartment and rapidly taken up into dentate granule cells, followed by Aβ_1–42-induced cognitive decline that is due to Zn²⁺ released from Aβ_1–42, suggesting that dentate granule cells are sensitive to extracellular Zn²⁺-dependent Aβ_1–42 toxicity. This paper deals with proposed vulnerability of the dentate gyrus to aging and Aβ_1–42 neurotoxicity.