The work of Wang and colleagues provides evidence that the effects of sleep deprivation on Aβ deposition and tau seeding and spreading and, conversely, the effects of AD pathology on sleep disruption are exacerbated by the presence of the APOE-ε4 allele, suggesting a feed-forward cycle that may be more detrimental and harder to break in the context of APOE4 (Figure 1). This evidence concerns the gene APOE and Alzheimer disease.