Is HCRTR2 a Genetic Risk Factor for Alzheimer's Disease?

Abstract

Backgrounds/Aims: Alzheimer's disease (AD) is one of the main types of dementia affecting about 50-55% of all demented patients. Sleep disturbances in AD patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble the core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. The aim of our study was to investigate whether genetic variants in the hypocretin (HCRT) and in the hypocretin receptors 1 and 2 (HCRTR1, HCRTR2) genes could modify the occurrence and the clinical features of AD and to examine if these possible variants influence the role of the protein in sleep regulation. Methods: Using a case-control strategy, we genotyped 388 AD patients and 272 controls for 10 SNPs in the HCRT, HCRTR1 and HCRTR2 genes. In order to evaluate which residues belong to the HCRTR2 binding site, we built a molecular model. Results: The genotypic and allelic frequencies of the rs2653349 polymorphism were different (χ² = 5.77, p = 0.016; χ² = 6.728, p = 0.035) between AD patients and controls. The carriage of the G allele was associated with an increased AD risk (OR 2.53; 95% CI 1.10-5.80). No significant differences were found in the distribution of either genotypic or allelic frequencies between cases and controls in the HCRTR1 polymorphisms rs2271933, rs10914456 and rs4949449 and in the HCRTR2 polymorphism rs3122156. Conclusion: Our data support the hypothesis that the HCRTR2 gene is likely to be a risk factor for AD. The increased risk inferred is quite small, but in the context of a multi-factorial disease, the presence of this polymorphism may significantly contribute to influencing the susceptibility for AD by interacting with other unknown genetic or environmental factors in sleep regulation.

Sleep disorders, obesity, and aging: The role of orexin

“…While many studies have focused on the importance of orexin loss in disease-related sleep disturbances, several recent reports suggest orexin may also play a role in some aspects of neurodegenerative disease pathogenesis. Orexin receptor 2 polymorphisms have been identified as a potential risk factor for development of AD (Gallone et al, 2014), however in another study loss of orexin neurons in narcoleptics failed to alter AD risk (Scammell et al, 2012). With respect to PD, the incidence of prior narcolepsy diagnosis was five times higher than expected in PD patients (Christine et al, 2012), suggesting that narcolepsy or narcolepsy treatments might influence development of PD.…”

Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease?

“…Degeneration of the orexin system in AD has long been recognized 110–112 . However, hypothalamic orexin dysfunction may actively contribute to AD pathophysiology; a possibility supported by the finding that individuals carrying a polymorphism of an orexin receptor gene show increased AD risk 113 . Nevertheless, controversies remain.…”

Metabolic and Non-Cognitive Manifestations of Alzheimer’s Disease: The Hypothalamus as Both Culprit and Target of Pathology

“…A postmortem study found lower orexin levels in the CSF and hypothalamus in AD (Fronczek et al, 2012), while other studies found increased or no significant changes (Liguori et al, 2014; Schmidt et al, 2013). Interestingly, a recent case-control study investigating genetic variants in the orexin or orexin receptor genes found that a polymorphism in the orexin receptor 2 gene increased the risk for AD (OR 2.53, 95%CI 1.10–5.80), suggesting that genetic variations in orexin signaling could contribute to AD susceptibility either through deficits in sleep regulation or another currently unknown mechanism (Gallone et al, 2014). One study interestingly found no significant difference in CSF orexin levels between AD and healthy control subjects, but CSF levels of melanin-concentrating hormone (MCH) were significantly elevated in AD subjects and correlated with CSF tau levels and severity of cognitive impairment (Schmidt et al, 2013).…”