Cerebrospinal fluid orexin in Alzheimer's disease: a systematic review and meta-analysis

Objective/background: A growing body of evidence suggests that sleep and Alzheimer's disease (AD) have a bi-directional relationship. Emerging research also suggests that orexin, a key neurotransmitter involved in sleep-wake regulation, may be altered in persons with AD, however results have not been consistent across prior studies. This investigation was conducted to both evaluate the aggregate literature to minimize the risk of bias and identify potential factors associated with heterogeneity across studies.

Methods: Systematic review identified relevant investigations that compared cerebrospinal fluid orexin in persons with AD and controls. Meta-analysis (random effects model) compared effect size (Hedge's g) for orexin between AD and controls. Meta-regression was additionally performed for key variables of interest to evaluate potential causes of heterogeneity among studies.

Results: 17 studies were identified that met inclusion/exclusion criteria. Evidence of publication bias was not identified. Non-significant increases in orexin were observed in AD relative to controls, with moderate to large heterogeneity among studies (Hedge's g = 0.20, p = 0.136, I² = 72.6%). Meta-regression demonstrated both year of publication (β = 0.055, p = 0.020) and effect size for phosphorylated tau in AD versus controls (β = 0.417, p = 0.031) were associated with differences in orexin.

Conclusions: Results do not support broad differences in orexin in AD compared to controls, however, evolving diagnostic criteria may have affected findings across studies. Future research that examines orexin in AD over the longitudinal course of the disorder and explores potential links between phosphorylated tau and orexin are indicated.