Figure 1. Sleep deprivation in the context of APOE4 results in a feed-forward loop that perpetuates neuropathological features and further disrupts sleep.

The APPPS1:E4 mouse model develops pathology, including dystrophic neurites around amyloid plaques. Sleep deprivation in APPPS1:E4 mouse models results in microglial dysfunction that worsens amyloid and tau pathology, leading to further sleep disruption in a feed-forward loop. Structural changes include increases in the amyloid plaque area and fewer microglia clusters around plaques, which causes greater dystrophic neurite formation. In the presence of AD-tau, increased dystrophic neurites lead to further tau seeding and spreading. In addition, altered astrocyte function and reduced polarization of AQP4 to endfeet on blood vessels can impair glymphatic clearance of Aβ and lead to a higher plaque load. The expression of microglial homeostatic genes is reduced, which could further increase the plaque load, decrease microglial clustering, and induce astrocytic changes such as AQP4 reduction. APOE4 may also directly affect astrocyte function, as it is highly expressed in astrocytes.