In this study the authors provide the first direct experimental evidence that the treatment of Tg2576 transgenic mice with an inhibitor of beta-secretase, GRL-8234, rescues the age-related cognitive decline. The authors demonstrated that the injected GRL-8234 effectively enters the brain and rapidly decreases soluble Abeta in the brain of Tg2576 mice. The rescue of cognition, which was observed only after long-term inhibitor treatment ranging from 5 to 7.5 mo, was associated with a decrease of brain beta amyloid- plaque load. In addition the authors found no accumulation of APP after several months of inhibitor treatment. These observations substantiate the idea that Abeta accumulation plays a major role in the cognitive decline of Tg2576 mice and support the concept of Abeta reduction therapy as a treatment of AD.