Diabetes causes the onset of amyloid pathology in a rabbit model and acts as a primary factor in inducing an earlystage AD phenotype. T2DM and AD share several common abnormalities, including aging-related processes, high cholesterol levels, metabolic disorders, Ab aggregation, tau protein phosphorylation, glycogen synthase kinase-3 over-activation, insulin resistance and the induction of oxidative stress. An intracerebroventricular infusion of streptozotocin is a valid experimental model to explore the etiology of sAD ; however, the mechanisms underlying ICV STZ-induced AD-like pathological changes remain elusive. Magnesium plays an important role in a wide variety of critical cellular processes, including oxidative phosphorylation, glycolysis, cellular respiration and protein synthesis. Magnesium depletion, particularly in the hippocampus, appears to represent an important pathogenic factor in AD. A decreased magnesium level is found in various tissues of AD patients in clinical and laboratory studies. A chronic reduction in dietary magnesium impairs memory, and the treatment of dementia patients with nutritional magnesium improves memory. A causal relationship between low magnesium in hippocampal neurons and impairments in learning ability has been demonstrated in aged rats. Recent studies have implicated that magnesium modulates the AbPP processing and that in the presence of high extracellular magnesium levels, AbPP processing CHIR-99021 stimulates the a-secretase cleavage pathway. Moreover, treatment with a novel compound, magnesium-L-threonate, regulates NMDAR signaling, prevents synapse loss, and reverses memory deficits in aged rats and AD model rats. Interestingly, hypomagnesemia is a common feature in T2DM patients, and magnesium deficiency has been proposed as a risk factor for T2DM. Therefore, magnesium is involved in AD and diabetes and may serve as a convergent point that links AD and diabetes. The present study produced a sAD adult rat model using an ICV infusion of STZ and investigated the effects of the simultaneous supplementation of magnesium sulfate on ICVSTZ-induced AD-like pathological changes, memory deficits, and the underlying mechanisms of AD pathology. We found that the simultaneous intraperitoneal injection of magnesium sulfate restored brain magnesium levels, prevented ICV-STZ-induced memory impairments and reversed long-term potentiation impairments with a concurrent increase in the expression of synapse-associated proteins and synaptic complexity. In addition, magnesium sulfate markedly decreased tau hyperphosphorylation at multiple AD sites in sAD rats by improving insulin sensitivity, and increasing the inhibitory phosphorylated GSK-3b through the activation of PI3K and Akt. The progression of AD from the early stages of the neurodegenerative process to symptomatic stages occurs over a long period of time, but the disease rapidly causes devastating effects once cognitive impairments appear. These facts highlight the need to search for treatments that act on selective targets during the silent period of the disease, which are aimed at retarding disease progression toward dementia.