Table 1.

Key features, predictions and proposed tests of the hypnic hypothesis of AD

Features	Predictions	Tests
Systems level
– Pathology in brainstem pathways critical for sleep-wake and circadian physiology – Pathological changes in brainstem nuclei implicated in circadian control – Dysfunction and degeneration of ascending neurotransmitter pathways – Altered sleep/circadian physiology	– Histopathological analyses in presymptomatic subjects – Functional, tractographic studies of brainstem pathways – Longitudinal sleep analysis in presymptomatic subjects – Animal models (especially transgenic)
– Sleep disruption drives subsequent neurodegeneration	– Disrupted sleep/circadian patterns early in clinical course precedes cognitive decline, cortical dysfunction and atrophy	– Longitudinal sleep analyses in presymptomatic subjects with parallel neuroimaging – Early intervention to ameliorate sleep disruption – Epidemiological studies assessing effects of premorbid neuronal activity (e.g. occupation, educational attainment) – Animal models (especially transgenic)
– DMN neurodegeneration linked with sleep disruption	– Specific DMN dysfunction, disintegration correlated with sleep/brainstem indices	– Functional, structural neuroimaging of DMN against behavioural indices in relation to sleep analyses
– REM sleep is an active ‘rescue’ state	– REM deprivation and augmentation effects on cognitive/neuronal function	– Sleep analyses in AD subjects – Animal models with selective REM deprivation
– Self-amplification of sleep disruption effects	– Neurodegeneration and sleep alteration accelerating in tandem	– Longitudinal sleep analyses, cognitive tests, neuroimaging in AD subjects – Sleep parameters manipulated in animal models
Cellular level
– Sleep disruption drives pro-inflammatory and oxidant states	– Pro-inflammatory, pro-oxidant responses correlated with circadian indices	– Animal models with biochemical studies – Human plasma studies
– Sleep disruption drives protein misfolding and accumulation	– β-amyloid, tau levels correlated with circadian indices	– Interstitial and CSF β-amyloid and tau levels – Pathological studies with regional quantitation
– Cellular miscommunication drives neurodegeneration	– Persistent patterns of altered synaptic activity drives neurodegeneration	– Manipulate environment and neurochemistry (animal models) – Synthetic neural networks modelling sleep stage activity
Molecular level
– Altered expression of circadian genes predisposes to neurodegeneration	– Altered expression profiles of (e.g. circadian clock) gene effects on neurodegeneration	– Genomic, endophenotypic analyses – Transgenic animal models
– AD-related genes produce circadian alterations	– Primary alterations in circadian indices in at-risk individuals	– Sleep analyses in at-risk young subjects