Our recent findings in brain tissue from AD patients—which show that ApoE4, but not ApoE3, competes with TFEB to suppress lysosomal autophagy by directly binding to the CLEAR-DNA promoter site4—led us to posit that a small molecule that stably binds ApoE4 would disrupt its interaction with CLEAR-DNA motifs. Here, APOE is linked to Alzheimer disease.