To date, only a few randomized clinical trials (RCTs) have investigated the effects of omega-3 fatty acids (FA) on Alzheimer's disease (AD). Some of these studies demonstrated that patients with very mild AD or mild cognitive impairment benefit from omega-3 FA treatment, but none showed significant improvements in cognitive function in patients with moderate or advanced AD. All these RCTs had a relatively short duration of supplementation, however, and we hypothesized that this might be one of the reasons why no effects of omega-3 FA supplementation could be observed in patients with "moderate" or "advanced" AD. Animal studies offer better possibilities for controlled long-term supplementation than clinical studies. Therefore, we performed a systematic review (SR) and meta-analysis of the literature that focused on effects of the relatively long-term omega-3 FA supplementation (minimum period; 10% of average total lifespan) on cognitive impairment, amyloid-β pathology, and neuronal loss in animal models of AD. This SR shows that long-term omega-3 FA supplementation decreased the omega-6/omega-3 FA ratio and reduced the amount of amyloid-β in experimental animal models of AD. Omega-3 FA supplementation also improved cognitive function; this effect appeared larger in rats compared to mice, and in males compared to females. Moreover, omega-3 FA supplementation diminished the amount of neuronal loss, especially in female animals. The results of this SR indicate that it might be worthwhile to perform new clinical trials with long-term omega-3 FA supplementation in AD patients.