The pathological process of Alzheimer disease (AD) is closely related to energy metabolism disorders. In the nervous system, monocarboxylate transporter 4 (MCT4) is expressed in the glial cell membrane and is responsible for transporting intracellular lactic acid. In this study, we found that MCT4 expression was elevated in the cerebrospinal fluid of patients with mild cognitive impairment. Two- and three-month-old APPswe/PS1dE9 (APP/PS1) mice and C57 mice were studied. The APP/PS1 mice began to show cognitive decline at 3 months of age and MCT4 in the hippocampus of 2- and 3-month old APP/PS1 mice was higher than that of C57 mice. This change is similar to that in people with mild cognitive impairment. Subsequently, MCT4 overexpression/siRNA lentiviral particles were used to establish stable primary astrocytes. Overexpression and knockdown of MCT4 had no significant effect on glial cell apoptosis. Transfected astrocytes were co-cultured with neurons. Overexpression of cytoplasmic MCT4 increased the expression of Aβ42, γ-secretase, and CD147 in the co-culture system; in addition, the growth ability of primary neurons decreased significantly, extracellular lactic acid increased, and neuronal apoptosis increased. In AD model mice, siMCT4 injection improved cognitive ability, reduced neuronal apoptosis, and reduced γ-secretase expression. Taken together, these results suggest that MCT4 is involved in energy metabolism during early pathological processes in AD, and suppression of MCT4 represents a new potential neuroprotective factor for AD.