As noted previously by other investigators (
Aloia et al., 2004;
Beebe et al., 2003), these data confirm cognitive deficits associated with a measure of sleep apnea. However, unlike previous research, we have extended these findings as they apply to a population for whom impaired cognition serves as the primary focus of complaint, i.e., a memory clinic population. Sleep apnea is not assessed routinely in dementia clinics, and these data may be of importance because they imply that this possibly reversible form of cognitive impairment could be screened. Moreover, our data demonstrate that the concurrent presence of cardiovascular disease increases the likelihood of detecting such associations, whereas the absence of such medical comorbidities decreases the strength of those relationships. Sleep apnea is strongly associated with cardiovascular disease, including clinic-measured hypertension (
Endeshaw, Bloom, & Bliwise, 2008;
Newman, et al., 2001;
Nieto et al., 2000;
Shahar et al., 2001), nocturnal non-dipping of blood pressure(
Endeshaw, White, Kutner, Ouslander, & Bliwise, 2009), impaired endothelial function (
Nieto, Herrington, Redline, Benjamin, & Robbins, 2004), left ventricular dysfunction (
Chami et al., 2008), and even incident coronary heart disease (
Gottlieb et al., 2010) and stroke (
Arzt et al., 2005). Given such studies, our findings are compatible with a number of epidemiologic studies (see (
Qiu, Winblad, & Fratiglioni, 2005) for review) suggesting that hypertension confers risk for late life cognitive impairment. Well-known relationships between sleep apnea and glucose intolerance (
Punjabi et al., 2004) also are consistent with population-based studies suggesting that diabetes and insulin resistance are associated with cognitive impairments (
Kilander, Nyman, Boberg, Hansson, & Lithell, 1998;
Roberts et al., 2008;
Vanhanen et al., 1998). Viewed in this way, sleep apnea (defined in our study by a proxy measure, e.g., nocturnal desaturation), should be considered a correlate of cognitive impairment in a late life memory clinic population, probably equally as likely as these other medical comorbidities. The impairments most likely to be associated with sleep apnea in this study did not involve memory, but rather were in the domains of attention and concentration.
Given the potential importance of co-morbid cardiovascular disease in these results, it is not surprising that those few studies that have examined the role of apolipoprotein epsilon (APOE) genotype as an effect modifier in the association between cognition and sleep apnea have shown that the presence of one (
Cosentino et al., 2008;
O'Hara et al., 2005) or two (
Spira et al., 2008) E4 alleles confer risk and moderate the association. Data also suggest that sleep apnea per se may be associated with the E4 allele (
Kadotani et al., 2001), though those associations may be age-dependent (
Gottlieb et al., 2004). APOE genotyping was not available in our patients to test this association here. However, the poorer recovery from intracerebral and subarachnoid hemorrhage (
Martinez-Gonzalez & Sudlow, 2006) and more likely cognitive impairment subsequent to cardiac bypass surgery (
Tardiff et al., 1997) in E4 carriers are compatible with sleep apnea as a potential insult for decrements in higher order cognition in patients who have this vulnerability.
A limitation of our data is that we have relied exclusively on overnight ambulatory pulse oximetry for sleep apnea case identification. Nocturnal pulse oximetry is considered by the American Academy of Sleep Medicine a Level 4 measurement device for measurement of sleep apnea (
Collop et al., 2007). Obviously, individuals who have sleep disordered breathing but who do not show arterial oxygen desaturation would be missed by such measurements. Such imputed high sensitivity accompanied by more modest specificity has been documented in many studies (
Series et al., 1993;
Yamashiro & Kryger, 1995), though a convincing case has been made for such an application as a “first tier” screening approach for initial identification of possible sleep apnea (
Netzer, Eliasson, Netzer, & Kristo, 2001). As we mentioned previously, we have had success (96% usable data) adopting this procedure into the routine evaluation of our memory clinic population, who then can be followed up with a more detailed full polysomnographic evaluation, perhaps with eventual referral for nasal continuous positive airway pressure (CPAP). Although the two measures of oxygen desaturation can be differentiated (
Chesson, McDowell Anderson, Walls, & Bairnsfather, 2001), our data largely suggest that both measures yielded similar associations with neurocognitive measures.
Regarding CPAP treatment for sleep apnea, although randomized clinical trials (RCTs) currently exist in patients with hypertension, congestive heart failure and diabetes, only one published RCT has been published attempting to treat dementia patients with sleep apnea with CPAP (
Ancoli-Israel et al., 2008). Although the results from that trial are modestly encouraging for improving neurobehavior (improvements in mood, sleepiness and sleep architecture were clearly evident), the study was underpowered, the effects on cognition were more limited, and the role of potential effect moderators (e.g., genotype, presence of cardiovascular disease) were not considered (
Bliwise, 2011). The current analyses imply that future intervention studies for sleep apnea focusing on cognition should select for patients with comorbid medical diseases.
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