By revealing the impaired CCZ1-MON1A GEF activity in AD models and showing that over-expression of CCZ1-MON1A promoted autophagosome maturation and alleviated autophagic substrates accumulation in cellular and mice models of AD, we show that modulation of CCZ1-MON1A expression or CCZ1-MON1A GEF activity can be an approach to restoring autophagosome maturation in AD. Here, CCZ1 is linked to Alzheimer disease.