Harnessing the immune system to clear protein aggregates is emerging as a promising approach to treat various neurodegenerative diseases. In Alzheimer's disease (AD), several clinical trials are ongoing using active and passive immunotherapy targeting the amyloid-β (Aβ) peptide. Limited emphasis has been put into clearing tau/tangle pathology, another major hallmark of the disease. Recent findings from the first Aβ vaccination trial suggest that this approach has limited effect on tau pathology and that Aβ plaque clearance may not halt or slow the progression of dementia in individuals with mild-to-moderate AD. To assess within a reasonable timeframe if targeting tau pathology with immunotherapy could prevent cognitive decline, we developed a new model with accelerated tangle development. It was generated by crossing available strains that express all six human tau isoforms and the M146L presenilin mutation. Here we show that this unique approach completely prevents severe cognitive impairment in three different tests. This remarkable effect correlated well with extensive clearance of abnormal tau within the brain. Overall, our findings indicate that immunotherapy targeting pathological tau is very feasible for tauopathies, and should be assessed in clinical trials in the near future.