Figure 1. Schematic of possible mechanisms underlying the reciprocal relationship between sleep disturbances and Alzheimer’s pathology.

In summary, sleep disturbances lead to increased waking neuronal activity-dependent Aβ and tau release, resulting in greater amyloid plaque and tau tangle deposition. Pathological proteins lead to neurometabolic uncoupling of lactate metabolism with the sleep–wake cycle, causing further sleep disturbances. Alzheimer’s disease pathology may also impact the immune system, continuing to feed forward alterations in sleep and subsequent pathology. Within the larger positive feedback cycle lies smaller positive cycles involving the default mode network, whose dysfunction exacerbates activity-dependent Aβ and tau, and impaired glia-lymphatic (‘glymphatic’) clearance of Aβ and tau, leading to increased Alzheimer’s disease pathology and astrocytic metabolic dysfunction.

Aβ: Amyloid-β.