Our study identifies Metformin as a novel CMA activator, sheds light on the mechanism of CMA activation by Metformin, and identifies APP as a novel CMA substrate, suggesting that Metformin-induced CMA activation and degradation of APP and Aβ can have beneficial effects in the context of pathogenesis of the Alzheimer’s disease. Here, APP is linked to early-onset autosomal dominant Alzheimer disease.