In summary, our results show that CMA activation by either Metformin treatment or overexpression of Hsc70 can decrease the insoluble Aβ1-42 burden, Aβ plaque levels, induce degradation of APP and alleviate cognitive deficits of the APP/PS1 model of Alzheimer’s disease. The gene discussed is APP; the disease is early-onset autosomal dominant Alzheimer disease.