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The amyloid-β (Aβ) oligomer, rather than the Aβ monomer, is considered to be the primary initiator of Alzheimer’s disease. It was hypothesized that p(Aβ3–10)10-MT, the recombinant Aβ3–10 gene vaccine of the Aβ oligomer has the potential to treat Alzheimer’s disease. In this study, we intramuscularly injected the p(Aβ3–10)10-MT vaccine into the left hindlimb of APP/PS1/tau triple-transgenic mice, which are a model for Alzheimer’s disease. Our results showed that the p(Aβ3–10)10-MT vaccine effectively reduced Aβ oligomer levels and plaque deposition in the cerebral cortex and hippocampus, decreased the levels tau protein variants, reduced synaptic loss, protected synaptic function, reduced neuron loss, and ameliorated memory impairment without causing any cerebral hemorrhaging. Therefore, this novel DNA vaccine, which is safe and highly effective in mouse models of Alzheimer’s disease, holds a lot of promise for the treatment of Alzheimer’s disease in humans.