Sleep apnea, APOE4 and Alzheimer's disease 20 years and counting?

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Abstract

Alzheimer's disease (AD) is acknowledged to be at least partially genetic, and one of the key genotypic markers for this condition is the APOE4 allele. Links between sleep apnea and AD have long been suspected because of mental impairment seen in some sleep apnea patients and possible evidence suggesting higher rates of sleep apnea in some dementia patients. The recent demonstration of an association between the APOE4 genotype and sleep apnea has rekindled further interest in this topic, particularly because sleep apnea is characterized by multiple genetic vulnerabilities. We review here evidence related to associations between sleep apnea and dementia, the role of APOE4 as a likely marker for cerebrovascular disease, and discuss treatment considerations relevant to sleep apnea as a potentially reversible cause of dementia.

Introduction

The recent study by Kadotani et al. [1] showing an association between the APOE4 genotype and sleep apnea has reawakened interest in a possible association between dementia and sleep apnea. APOE is a lipoprotein made in the liver and brain and is involved in cholesterol deposition and transport. Relationships between APOE subtypes (specifically the E4 allele) and Alzheimer's disease (AD) were first noted in 1993 [2] and have been confirmed many times. Follow-up studies noted dose relationships between the number of E4 alleles and late-onset AD, whereas the presence of E2 allele appeared protective [3], [4]. The specific function of APOE in the brain and the mechanism by which its genotype facilitates/protects for AD remains unclarified. The gene-coding region for this protein on chromosome 19 and its possible interaction with phosphorylated tau protein (specifically, enhanced binding of the E2 and E3 genotype, perhaps representing a protective effect) suggests that it may be a valuable genetic marker for at least some cases of AD [5]. Yet other findings have related APOE genotype to a different cardinal feature of AD neuropathology (beta amyloid deposition) [6].

Although the possibility that the APOE findings represent direct linkage of a gene or genes causing AD, this evidence is by no means conclusive. First, it must be recalled that although lipids have long been known to be a risk factor for cardiovascular disease [7] their role, and the role of APOE in particular, within the central nervous system may be exceedingly complex. For example, some data suggest that APOE expression is up-regulated in response to cerebral ischemia since its expression in astrocytes increases markedly following injury [8]. These results and associations between the APOE4 subtype and poorer recovery from cardiac by-pass surgery [9], hemorrhagic stroke [10] and head injury [11], all suggest that the APOE4 genotype may need to be examined more broadly as a marker of vulnerability for or the presence of cerebrovascular disease. This may be particularly relevant when discussing a disease with broad-reaching impact upon the entire cardiovascular system, such as sleep apnea. Additionally, although controversial, several studies have demonstrated associations between the APOE4 subtype and vascular dementia that are as strong as or, in some cases, even stronger than the relationships between APOE4 and AD [12], [13], [14], [15], findings that again suggest utility of this marker when discussing sleep apnea and dementia in late life. Still other studies have questioned the relevance of the relationship between APOE4 and AD, as the association may account for only a small proportion of AD community cases [16] when compared to clinical populations.

Although the Kadotani et al. finding of an association between sleep apnea and APOE4 has been questioned in its own right, because others could not replicate the result in different genetic populations [17], [18], the provocative nature of this finding, particularly with regard to the role of APOE and AD, and its recent publication in relation to the Fourth Milano International Symposium on the Epidemiology of Sleep Disorders (Sept. 3–5, 2001) suggest a timely reappraisal of the potential relationships between sleep apnea and dementia from this perspective.

Section snippets

Studies of sleep apnea in AD

The earliest published test of a relationship between sleep apnea and AD can be traced back to the 1980 report from Milan by Smirne et al. [19] who noted that, in a single-group, uncontrolled study with a small number of AD patients, sleep apnea appeared to be highly prevalent. Following Smirne et al. were a number of studies throughout the mid- to late 1980s of small groups of AD patients and age-matched controls. The results from these studies were inconclusive, inasmuch as some studies

Studies of mental function in sleep apnea

A complementary but alternative approach relevant to examining associations between sleep apnea and AD focuses on the cognitive symptoms of the sleep apnea condition itself. Historically, observations in this domain can be traced back to the early work of Guilliminault et al. [25] who, in their original clinical description of sleep apnea, noted that 11 of 15 middle aged, sleep apnea patients showed “intellectual deterioration.” Subsequent to this, studies by Kales et al. [26] and Yesavage et

Plausibility of mechanism

Any consideration of a common genotype underlying a relationship between AD and sleep apnea also should consider what other mechanisms might underlie the phenotypic expression of both conditions. In fact, elucidation of potential mechanisms may hold substantial import for fully appreciating the nature of how relationships between dementia and sleep apnea might occur. One possible pathway mechanism involves the effects of hypoxia on acetylcholine neurotransmission within the central nervous

Treatment studies

A final consideration when discussing vascular dementia and sleep apnea is the potential for successful interventions. Partial functional recovery subsequent to many kinds of stroke is widely recognized, and, in the case of vascular dementia associated with sleep apnea, the possibility that interventions could be beneficial for mental function has precedent in treatment studies of sleep apnea and cognition in somewhat younger, nondemented patients. Valencia-Flores et al. [79] have shown, for

Integration of a provisional model describing sleep apnea and dementia

A revised model demonstrating potential relationships between sleep apnea and dementia is offered in Fig.1. This model builds on evidence presented elsewhere in this paper that suggests (a) only minimal differences between AD patients and controls with respect to their relative rates of sleep apnea; (b) well-defined cognitive deficits measured psychometrically associated with sleep apnea; (c) increased likelihood of cerebrovascular events in sleep apnea, probably related to hemodynamic changes

Acknowledgements

This study was supported by grants AG-10643, AG-06066 and NS-34545.

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      Finally, since the prevalence of OSAS is higher among patients with dementia than among the general population (Hoch et al., 1986; Ancoli-Israel et al., 1991; Sharafkhaneh et al., 2005; Rongve et al., 2010; Kim et al., 2011), it has been hypothesized that OSA may contribute to the development of dementia. OSA and dementia share common risk factors, including the presence of apolipoprotein e4 allele (APOE4) (Bliwise, 2001). This genetic risk factor for Alzheimer's disease and cognitive impairment (Strittmatter et al., 1993; Caselli et al., 2004; Crean et al., 2011) has also been associated with increased risk for OSA (Kadotani et al., 2001; Gottlieb et al., 2004).

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