1. Trends in Biomedical Science Theories of Alzheimer’s Disease

2. Roh et al. report a positive feedback loop between sleep-wake irregularities and aggregation of β- amyloid (Aβ) peptide, suggesting that sleep alterations could be an early event in Alzheimer’s disease (AD).

3. Age Sleep amount and quality decline with age. This effect is more in AD patients. Aβ aggregation increases during AD and is associated with a decline in sleep. Sleep amount/quality Αβ aggregation

4. In the absence of Aβ aggregation, ISF Aβ in mice and CSF Aβ in humans show diurnal oscillations associated with sleep (S) and awake (W) states. Following Aβ aggregation, the diurnal oscillation of Aβ is lost in mice and the animals spend more time awake (↑W). Whether the loss of diurnal CSF Aβ associated with Aβ aggregation contributes to increased wakefulness in humans with early AD is not known yet. No Αβ aggregation +Αβ aggregation

8. ApoE derived from astrocytes and other glial cells is believed to facilitate Aβ clearance in the extracellular space of the brain. In the absence of Aβ aggregation, there is coupling of lactate with diurnal oscillations in ISF Aβ, and a normal sleepwake rhythm. The astrocyte-neuron- lactate shuttle hypothesis posits metabolic coupling of the sleep-wake cycle to astrocyte function.

10. In this model, lactate metabolic coupling with diurnal oscillation of Aβ would be lost after Aβ aggregation, and wakefulness would increase. One way that coupling could be lost is that astrocytes responsible for clearing Aβ and also glutamate become mobilized by Aβ plaques, moving toward the plaques and away from neurons. This could initiate a positive feedback loop in which astrocytes would no longer metabolize Aβ or glutamate from nearby neurons, leading to further aggregation of Aβ and increased excitotoxicity and neuronal injury due to glutamate accumulation.

12. Pathways by which apoE and Ab interact in the brain. ApoE is primarily produced by both astrocytes and microglia and is subsequently lipidated by ABCA1 to form lipoprotein particles. In the extracellular space, lipidated apoE binds to soluble Ab and influences the formation of amyloid plaques and transport of Ab within the CNS. ApoE is endocytosed into various cell types within the brain by different members of the LDL receptor family. ApoE may also facilitate the cellular uptake of Ab through the endocytosis of a complex of apoE-containing lipoprotein particles bound to Ab. Furthermore, apoE has been shown to directly enhance both the degradation of Ab within microglial cells and the ability of astrocytes to clear diffuse Ab deposits