Amyloid β oligomers (AβO)-induced alterations in synaptic structure and function was proposed to be implicated in early cognitive impairment in Alzheimer’s disease (AD), long before evident neurodegeneration took place. Thus, specifically targeting AβO by immunotherapy could be an alternative for AD treatment. McGill-R-Thy1-APP transgenic rats with human APP bearing the Swedish and Indiana mutations (of familial AD) in homozygous (+/+) condition, was reported to show cognitive deficits at 3 months. Meanwhile, heterozygous (+/-) rat showed a more subtle and slower developing phenotype, though with consistent memory impairment in 4 month old males. We aimed to evaluate the efficacy of an anti-AβO single-chain variable fragment antibody (NUsc1) expressed from an adeno-associated (AAV) viral vector, to prevent that memory impairment. Two month-old (+/-) rats received an ICV injection of that AAV-NUsc1, which drives neuronal expression of NUsc1. After 2 months, long-term memory (LTM) performance was assessed in either injected or not Tg females and males, and their wt littermates. Both Tg and wt females showed similar LTM performance. Instead, Tg males showed LTM deficits, while those vector-treated expressed LTM as wt rats, indicating that AAV-NUsc1 was able to prevent such deficits. Using same AAV-NUsc1 in different mouse AD models we had also shown STM improvement. Therefore, this sort of immunotherapy emerges as a novel promising experimental tool for AD treatment.