Immunotherapy with A is expected to bring great improvement for Alzheimer disease (AD). However, clinical trials have been suspended because of meningoencephalitics, which accompanied lymphocytic infiltration. We have developed an oral vaccine for AD with a recombinant adeno-associated viral vector carrying A cDNA (AAV/A). The vaccine reduces the amount of A deposited without lymphocytic infiltration in APP transgenic (Tg2576) mice. In the present study, Tg2576 mice showed progressive cognitive impairments in the novel object recognition test, Y-maze test, water maze test, and contextual conditioned fear learning test. A single oral administration of AAV/A to Tg2576 mice at the age of 10 months alleviated progressive cognitive impairment with decreased A deposition, insoluble A, soluble A oligomer (A*56), microglial attraction, and synaptic degeneration induced in the brain regions at the age of 13 months. A histological analysis with hematoxylin and eosin and an immunohistochemical analysis with antibodies against CD3, CD4, CD8, and CD19 suggested there was no lymphocytic infiltration or microhemorrhage in the brain of AAV/A-vaccinated Tg2576 mice at 13 months of age. Taken together, these results suggest that immunotherapy with AAV/A is a safe and effective treatment for AD.--Mouri, A., Noda, Y., Hara, H., Mizoguchi, H., Tabira, T., Nabeshima, T. Oral vaccination with a viral vector containing A cDNA attenuates age-related A accumulation and memory deficits without causing inflammation in a mouse Alzheimer model.