Sabbagh MN et al. – Robust preclinical in vitro and in vivo data indicate that latrepirdine has a protective effect against neurotoxic changes, increasing the survival of neurons, inhibiting mitochondrial permeability and reducing mitochondrial instability. Phase I–III studies show demonstrable safety and minimal toxicity in subjects treated with latrepirdine. A Phase II study demonstrated statistically significant cognitive and behavioral improvement in the treatment group and cognitive and behavioral decline from baseline in the placebo group in Russian Alzheimer’s disease subjects. However, the Phase III monotherapy multinational study failed to reproduce a robust clinical efficacy signal. The reasons for treatment failure are most likely due to the placebo group failing to decline as expected, the proposed mechanism of action maybe not having an effect on the Alzheimer’s disease process and the data in Phase II being incongruous owing to significant disparities in the populations recruited in the Phase II compared with the Phase III trial.