Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome: Amyloid-β and Tau Imaging

1 Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-180640 IOS Press oo f Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome: Amyloid-␤ and Tau Imaging Pr Alby Eliasa,e,∗ , Tia Cumminsa , Regan Tyrrella , Fiona Lamba , Vincent Doreb , Robert Williamsc , Jeffrey Rosenfeldd , Malcolm Hopwoode , Victor L. Villemagnea and Christopher C. Rowea a Department of Molecular Imaging and Therapy, Austin Health, The University of Melbourne, Victoria, Australia b CSIRO Brisbane, Queensland, Australia Brain Centre, Parkville, Victoria, Australia d Department of Neurosurgery, Monash University, Victoria, Australia e Department of Psychiatry, The University of Melbourne, Victoria, Australia uth or c Melbourne Accepted 31 August 2018 co rre cte dA Abstract. Background: An association between obstructive sleep apnea (OSA) and Alzheimer’s disease has been suggested but little is known about amyloid-␤ and tau deposition in this syndrome. Objective: To determine amyloid and tau burden and cognitive function in OSA in comparison to those without a diagnosis of OSA. Methods: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio (SUVR) of 18 F-florbetaben and 18 F-AV1451, to quantify amyloid and tau burden. Results: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18 F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35 ± 0.21 versus 1.27 ± 0.16, p = 0.04). There were more apolipoprotein E ␧4 allele (APOE ␧4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18 F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ␧4 was adjusted. The reported use of CPAP (n = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18 F-AV1451 uptake between the two groups. Conclusions: Obstructive sleep apnea is associated with Alzheimer’s disease pathology, but this relationship is moderated by APOE ␧4 and BMI. INTRODUCTION Un Keywords: Alzheimer’s disease, amyloid PET, dementia, obstructive sleep apnea, tau PET Alzheimer’s disease (AD) is the most common cause of dementia [1, 2]. The precise mechanism of ∗ Correspondence to: Alby Elias, 343 Burwood Hwy, East Burwood, 3151 Victoria, Australia. Tel.: +61 417325223; Fax: +61 3 98725964; E-mail: alby.elias@unimelb.edu.au. the disease is still unknown, but investigations over the past several decades have identified numerous risk factors for AD [3–9]. Age is the strongest risk factor for AD and genetic factors posit substantial risk [5, 7, 8]. Neuritic plaques and neurofibrillary tangles (NFT) are the two cardinal lesions of AD. The plaque contains a central core of amyloid-␤ (A␤) and NFT are intracytoplasmic fibrillar structures composed of ISSN 1387-2877/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved A. Elias et al. / Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome or Pr oo f neuropsychological examination, apolipoprotein E (APOE) ␧4 status, vascular risk factors, and A␤ and tau imaging. For the analysis of cognitive functions, subjects with traumatic brain injury (TBI) were excluded given its impact on cognitive outcomes. All subjects were screened for a history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP) mask. This history was corroborated by documentation from the primary care doctor of participants whenever possible. Those with no polysomnographic diagnosis of OSA or symptoms of OSA were the controls. Considering the poor sensitivity of the global score of PSQI in detecting OSA [23], the global score was not used to diagnose OSA but positive responses to the individual items-cessation of breathing during sleep and excess daytime sleepiness-were exclusion criteria for controls. uth Assessment of cognitive functions and vascular risk factors The neuropsychological examination included Logical Memory subset test 1 and 2 of Wechsler Memory Scale (WMS) – Anna Thompson story only [24], digit span forward and backwards from the Wechsler Adult Intelligence Scale third edition [25], categorical fluency test from the Delis-Kaplan Executive Function System [26], Rey Osterrieth Complex Figure Test (ROCFT) [27] and Trail Making Test parts A and B [28]. Vascular risk factor score was calculated by giving one point to each of the following: Diabetes mellitus, hypertension, coronary artery disease, hypercholesterolemia, body mass index (BMI) above 30, current smoking status, previous history of stroke, and atrial fibrillation. Sum of all points gave cumulative vascular risk. rre cte abnormally phosphorylated tau proteins [10, 11]. Given that amyloid plaques and NFT are cardinal lesions in AD, positron emission tomographic (PET) imaging using specific radioactive ligands that bind to amyloid and tau is a useful technique to evaluate the risk factors of AD. 18 F-florbetaben and 18 F-AV1451 are radio-ligands that have specific affinity for A␤ and 3R4 R tau aggregates, respectively [12, 13]. Sleep disorders have been investigated as potential risk factors for AD. Obstructive sleep apnea (OSA) is a syndrome that is diagnosed in the presence of clinical symptoms, most commonly excess daytime sleepiness in conjunction with an apnea-hypopnea index (AHI) greater than 5 events per hour [14]. The prevalence of OSA in community-based cohorts has been estimated as 2%–8% and it increases with age [15, 16]. Early studies demonstrated an association between AD and sleep apnea and a correlation between the severity of apnea and dementia [17, 18]. Recent investigations have demonstrated a link between A␤ deposition and sleep disturbances [19]. OSA is associated with earlier onset of both mild cognitive impairment (MCI) and dementia compared to subjects without OSA [20]. In a small sample of five patients with MCI, higher AHI and oxygen desaturation index were associated with greater amyloid deposition [21]. However, little is known about A␤ and tau imaging in cognitively asymptomatic individuals with OSA. In the present study, we report cognitive function and A␤ and tau imaging findings in cognitively asymptomatic patients with OSA. dA 2 METHODS Participants recruitment Un co This was a cross-sectional study evaluating AD risk in community-based Vietnam Veterans. Veterans were recruited via the Older Veterans Psychiatric Program of the Repatriation Hospital, Austin Health and advertisement in magazines and newsletters of Retired Service League and the Vietnam Veterans Association of Australia. The institutional review board of Austin Health, a major metropolitan health service in Melbourne provided ethical approval for the study. Presence of dementia, existing diagnosis of MCI, psychotic and bipolar affective disorder, current substance abuse, and any unstable medical condition that could have impacted cognitive performance or made participation difficult were exclusions. Assessment consisted of medical history, Pittsburgh Sleep Quality Index (PSQI) [22], PET imaging The participants underwent a 20-min PET scan (4 x 5-min frames of emission data collected) acquired 90 min after a slow IV bolus administration of 250 MBq (±10%) of 18 F-florbetaben and 70 min after the injection of 370 MBq of 18 F-AV1451. Acquisition was performed with a Siemens PET/CT mCT128 and CT attenuation correction was applied. Image reconstruction used the Ordered Subset Expected Maximization (OSEM) algorithm. There was no correction for partial volume effect. 18 F-florbetaben and 18 F-AV1451 PET were both analyzed with Computational Analysis of PET from AIBL (CapAIBL) 3 A. Elias et al. / Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome p 67.69 ± 5.37 Males = 42 Females = 0 11.43 ± 2.78 34.2% (n = 35) 2.37 ± 1.18 32.56 ± 4.05 68.30 ± 3.86 Males = 77 Females = 0 11.70 ± 2.85 15.9% (n = 69) 1.43 ± 1.16 27.82 ± 4.03 0.47 Statistical analyses The continuous variables viz., 18 F-florbetaben and SUVRs and neuropsychological test scores were analyzed using independent t test while the categorical variables, OSA and APOE ␧4 status, were analyzed by Chi-square test. All tests were two-tailed with 95% confidence interval. Pearson correlation was used to find correlates of both 18 F-florbetaben and 18 F-AV1451 SUVRs and cognitive test scores. Multilinear regression analysis was then performed with explanatory variables found to be correlated and associated with 18 F-florbetaben or 18 F-AV1451 SUVRs and cognitive scores. 18 Fflorbetaben and 18 F-AV1451 SUVRs and cognitive scores were treated as the dependent variables. General linear model was used to test the interaction between OSA and amyloid and tau tracer SUVRs and a visually positive amyloid scan in predicting cognitive function. Un co 18 F-AV1451 oo Pr RESULTS Between March 2014 and June 2017, 170 veterans underwent screening after providing informed consent. From the consecutive sample, 44 veterans were excluded: 11 veterans had medical morbidities making participation difficult; seven met criteria for alcohol abuse; five had existing diagnosis of MCI; five could not cope with psychiatric assessment because of post-traumatic stress disorder and perceived stress; one had bipolar affective disorder; one had claustrophobia; and 14 withdrew from the study because of inconvenience. After exclusion 126 male veterans completed neuropsychological assessments and scans. Seven veterans reported symptoms of OSA according to PSQI but they did not have polysomnographic evaluation and they were therefore excluded from the analyses. The data from the remaining 119 veterans were analyzed. A polysomnographically confirmed diagnosis of OSA was present in 42 (35.2%) subjects. The characteristics of participants are shown in Table 1. Twenty-four patients reported regular use of CPAP; 14 veterans did not use CPAP; and use was indeterminate in four subjects. The mean duration between the diagnosis of OSA and the study assessment was 74.35 ± 27.06 months. Veterans with OSA had significantly higher vascular risk factor score compared with those without OSA (2.37 ± 1.18 versus 1.43 ± 1.16, p < 0.001, CI = –1.45 to –0.42). BMI was significantly higher in the OSA group than in the controls (32.56 ± 4.05 versus 27.82 ± 4.03, p < 0.001). There was no significant difference in age or years of education between the OSA and the control group (Table 1). The characteristics of OSA has been shown in Table 2. Veterans with OSA and controls did not differ significantly in the following cognitive functions: Digit span, categorical fluency, Logical Memory Test 1 and 2, ROCFT, ROCFT 3-min and 30min delayed recall. However, subjects with OSA scored significantly higher on Trail Making Test A rre cte software developed by the Commonwealth Scientific and Industrial Research Organization (CSIRO) [29]. CapAIBL allows quantitative PET measurements without relying on magnetic resonance imaging [30]. Global A␤ and regional tau burden were calculated by standardized uptake value ratio (SUVR) using cerebellar grey matter uptake as the reference. 18 FFlorbetaben scans were also read visually according to the manufacturer’s instructions by three readers and the classification into negative or positive scan was based on majority results. 18 F-AV1451 regional uptake in three regions was calculated by CapAIBL software: Mesial temporal (amygdala, hippocampus, entorhinal cortex, and parahippocampus); temporoparietal (inferior and middle temporal lobe, fusiform gyrus, posterior cingulate/precuneus, superior and inferior parietal and lateral occipital cortex); and rest of the neocortex. A visual read of 18 FAV1451 images was not performed as a standard method has yet to be developed. 0.62 χ2 = 4.53, p = 0.03 p < 0.001 p < 0.001 or Education in years Apolipoprotein E ␧4 Vascular risk factor score BMI Non-OSA group (n = 77) uth Age Gender OSA group (n = 42) dA Variables f Table 1 Patients characteristics in OSA 4 A. Elias et al. / Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome f oo (time to completion in seconds: 41.81 ± 12.54 versus 35.63 ± 11.69, p = 0.03, CI = –11.80, to –0.544) and B (time to completion in seconds: 126.70 ± 82.47 versus 97.95 ± 33.79, p = 0.03, CI = –54.29 to –3.22) (Table 3). Both test scores positively correlated with vascular risk factor score (r = 0.24, p = 0.03; r = 0.22, p = 0.04, respectively). The significant relation between OSA and Trail Making Test B did not stay when Trail Making Test A, a measure of visual attention and processing speed was controlled (R2 = 0.23, p = 0.12). The significance of OSA in predicting Trail Making Tests A (R2 = 0.118, p = 0.04) remained upon controlling the effects of age, education and APOE ␧4, but not when vascular risk factor score was adjusted for (R2 = 0.07, p = 0.16). In the general linear model analysis, there was no significant interaction between 18 F-florbetaben SUVR and OSA or visually positive 18 F-florbetaben scan and OSA in predicting either Trail Making Test A or B. Pr 6 years 24 85.5% (74%–93%) 33.0 (6–89) or Mean duration of diagnosis Regular CPAP users Mean nadir oxygen saturation Apnea-hypopnea Index uth Variables The boxplots for the distribution of 18 F-florbetaben SUVR are given in Fig. 1. Independent t test showed that the SUVR of 18 F-florbetaben was significantly higher in the OSA group than in the control group (1.35 ± 0.21 versus 1.27 ± 0.16, p = .04, CI = –0.14 to –0.003). A greater number of subjects with a visually positive 18 F-florbetaben scan in the OSA group did not reach significance between the OSA and control groups (29.7% versus 17.3%, χ2 = 2.26, p = 0.13). There was no significant increase in 18 F-AV1451 SUVR in OSA in any regions studied (Table 3). BMI significantly and positively correlated with 18 F-florbetaben SUVR (r = 0.341, p < 0.001) which was significantly higher in those with obesity (BMI more than 30, n = 48) compared with those who were non-obese (1.37 ± 0.22 versus 1.25 ± 0.13, p < 0.001). Vascular risk score showed significant positive correlation with global SUVR of 18 F-florbetaben (r = 0.206, p = 0.049) and regional SUVRs of 18 F-AV1451 in mesial temporal (r = 0.327, p = 0.004) and temporoparietal (r = 0.26, p = 0.03) regions. When separate analysis was done for the OSA group there was no significant difference between veterans who were regularly using CPAP and the non-users of CPAP in global 18 Fflorbetaben (1.36 ± 0.23 versus 1.35 ± 0.22, p = 0.82) or regional 18 F-AV1451 SUVRs. Baseline sleep diagnostic reports were available for 14 subjects. The dA Table 2 Characteristics of OSA rre cte Table 3 Cognitive tests scores in OSA Cognitive tests Un co Digit span 3-min delayed visual recall 30-min delayed visual recall Categorical fluency Trial Making Test A test, time to completion Trail Making Test B test time to completion (s) Recognition Logical Memory Test 1 Logical Memory test 2 Rey Copy Figure Test 18 F-florbetaben OSA group (n = 27) Non-OSA group (n = 56) p 15.78 ± 3.50 17.21 ± 4.98 17.32 ± 4.91 19.44 ± 5.59 41.81 ± 12.54 17.09 ± 4.17 16.28 ± 6.73 16.28 ± 6.73 21.41 ± 4.82 35.63 ± 11.69 0.16 0.53 0.21 0.10 0.03 126.70 ± 82.47 97.95 ± 33.79 0.03 20.03 ± 2.21 11.85 ± 4.65 10.85 ± 4.37 29.74 ± 6.39 20.50 ± 1.67 13.30 ± 4.29 11.37 ± 4.37 29.88 ± 2.66 0.30 0.16 0.61 0.88 Table 4 and 18 F-AV1451 SUVR Tracer SVURs OSA (n = 36) Non-OSA (n = 70) p (95% CI) 18 F-florbetaben 1.35 ± 0.21 1.24 ± 0.14 1.18 ± 0.10 1.20 ± 0.10 1.27 ± 0.16 1.19 ± 0.12 1.15 ± 0.08 1.17 ± 0.09 0.04 0.09 0.14 0.11 18 F-AV1451 Mesial temporal 18 F-AV1451 Neocortical 18 F-AV1451 Temporoparietal 5 Fig. 1. 18 F-florbetaben SUVR in OSA and controls. OSA in predicting 18 F-florbetaben SUVR remained significant upon controlling for vascular risk score (R2 = 0.10, p = 0.04) and age (R2 = 0.07, p = 0.03). Similarly, APOE e4 continued to be a significant predictor of 18 F-florbetaben SUVR when age (R2 = 0.08, p = 0.02) and vascular risk score (R2 = 0.10, p = 0.04) were adjusted. OSA did not retain its significance in predicting a visually positive 18 F-florbetaben scan (R2 = 0.11, p = 0.12) or 18 F-florbetaben SUVR (R2 = 0.145, p = 0.971) when APOE ␧4 or BMI was added while APOE ␧4 (p = 0.037) and BMI remained significant (p = 0.010). In the general linear model there was no significant interaction (F = 0.11, p = 0.73) between APOE ␧4 and OSA in predicting 18 F-florbetaben SUVR (Fig. 2). Un co rre cte negative correlation between nadir oxygen saturation and 18 F-florbetaben SUVR did not reach statistical significance (r = –0.563, p = 0.140). There was no significant correlation between AHI and 18 Fflorbetaben SUVR (r = –0.316, p = 0.317). APOE ␧4 carrier status was available for 104 veterans. There was increased rate of APOE ␧4 allele in the OSA group compared with the controls (34.2% versus 15.9%, χ2 = 4.53, p = 0.03). The SUVR for 18 F-florbetaben was significantly higher in the APOE ␧4 carriers than in the non-carriers (1.41 ± 0.21 versus 1.27 ± 0.17, p = 0.02). There were more visually positive 18 F-florbetaben scans in APOE ␧4 carriers than in non-carriers (50% versus 13.2%, χ2 = 14.17, p < 0.001). The SUVR of 18 F-AV1451 did not show a significant difference between APOE ␧4 carriers and non-carriers in any regions. In the multilinear regression analysis with 18 F-florbetaben SUVR as the dependent variable, vascular risk factor score and APOE ␧4 were added to OSA because these variables showed association and correlation with 18 F-florbetaben SUVR. Age was also added in view of its well-known correlation with amyloid deposition. The significance of dA uth or Pr oo f A. Elias et al. / Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome DISCUSSION Cognitive functions The cognitive functions previously reported to be impaired in OSA include attention, procedural memory and episodic memory [31–33], processing speed A. Elias et al. / Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome dA uth or Pr oo f 6 rre cte Fig. 2. Interaction between OSA and APOE ␧4: In the presence of APOE ␧4, amyloid burden was more greatly increased in OSA. Un co [34], spatial memory [33], and executive function [35, 36], Executive dysfunction has been reported in Vietnam veterans with OSA [35]. Language ability and psychomotor functions remain relatively unaffected. In the present study, subjects with OSA performed poorly on Trail Making Tests A and B. The Trail Making Test A measures visual attention and processing speed whereas Trail Making Test B assesses executive function. Felver-Gant et al. reported impaired performance on Trail Making Test B in OSA [35]. We have replicated this finding in subjects with OSA, but when we controlled for the score of Trail Making Test A, the effect of visual attention and processing speed the significance of Trail Making Test B did not remain indicating that the deficit was actually in processing speed rather than executive function. The association between OSA and impairment in these cognitive domains was independent of age, APOE ␧4, and education of the subjects, but not vascular risk burden, which was associated with OSA. The confounding effect of vascular burden was not adequately addressed in previous studies. A review of cognitive deficits in OSA has revealed varying cognitive deficits across studies [37]. The pattern of cognitive deficits varied according to the assessment settings (community cohorts against sleep medicine clinic), treatment with CPAP and age [38, 39]. A study that compared cognitive functions between young and older individuals found more attentional deficits in the older patients, a pattern supported by our study [37]. Sleep apnea and Alzheimer’s disease Apart from cognitive impairment, existing data suggest an association between OSA and MCI and dementia. A seminal longitudinal study found a twofold risk for MCI or dementia in patients with OSA over five-year follow-up [20]. Following early observations of association between OSA and dementia 7 A. Elias et al. / Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome uth or Pr oo f Low-Density Lipoprotein (VLDL) receptor more slowly than A␤-APOE ␧2 and A␤-APOE ␧3 complexes leading to decreased clearance of A␤ with APOE ␧4 [44]. In general population and clinical samples, OSA was found to be associated with the APOE ␧4 allele [45–47] but other studies and a metaanalysis did not find such an association [48]. We found a significantly increased rate of APOE ␧4 in OSA in our sample but the significantly increased A␤ tracer retention in OSA was no longer observed when the effect of APOE ␧4 was controlled. APOE ␧4 had stronger association with A␤ burden than OSA. The influence of OSA on 18 F-florbetaben SUVR was higher in the presence of APOE ␧4, than in its absence (Fig. 2). We did not find a significant difference in tau retention between the OSA group and controls but considering that cortical tau deposition follows A␤ accumulation and may be more closely associated with cognitive deficits, or dementia, this is not unexpected as our sample excluded subjects with MCI. Limitations dA While the diagnosis of OSA was made with polysomnographic studies, subjects without a diagnosis of OSA did not have laboratory sleep evaluation. The corollary is that some of the control subjects may have undiagnosed OSA. Therefore, the control group is not really a group without OSA; rather it is a group without symptoms of OSA. In our study we used PSQI, a sleep questionnaire that elicits symptoms of arrested breathing during sleep and daytime sleepiness. One study has reported that PSQI has poor sensitivity (38%) in screening for OSA, but this study used global PSQI score, not the responses to individual questions that are most relevant to OSA [23]. We excluded the participants who reported symptoms of OSA on PSQI. The rate of OSA in our sample (35.2%) is higher than the prevalence of OSA reported in the older general community (17%–24%) suggesting that Australian Vietnam veterans are well monitored for this condition and at low risk for missed diagnosis [49]. Our sample was primarily veterans with military deployment. This may limit generalizability of the above findings. The correlational analysis between nadir oxygen saturation and 18 F-florbetaben SUVR involved a small sample and type II error needs to be considered in this context. It is noteworthy that the subject with highest 18 F-florbetaben SUVR (2.01) had the lowest oxygen saturation (74%). Therefore, an association between oxygen desaturation and A␤ in OSA cannot be ruled out. Un co rre cte further findings have accrued recently supporting the link between sleep disordered breathing and both MCI and dementia [18–20]. A recent study demonstrated annual decline in the level of cerebrospinal fluid (CSF) A␤42 over a two-year period in cognitively asymptomatic elderly patients with OSA, implying increased risk of AD in this condition [40]. The change in CSF A␤42 correlated with the severity of OSA independent of APOE. However, there was no association between OSA and increased amyloid uptake on PET scan. The results of the present study show that patients with a polysomnographic diagnosis of OSA have slight but significantly higher global uptake of 18 F-florbetaben compared to subjects without a diagnosis OSA. This association was independent of age and vascular risk factors, but not APOE ␧4 or BMI. Both BMI and APOE ␧4 were associated with 18 F-florbetaben SUVR. Previous studies have suggested a negative correlation between BMI and amyloid load [41, 42]. The relationship between dementia and BMI is two-phased, increased risk of dementia was seen with BMI when weight was measured 20 years or more prior to dementia diagnosis and this association was reversed when weight was measured in 10 years or less before dementia diagnosis [43]. The first phase may represent a causal effect of obesity on dementia and the second phase is due to weight loss from metabolic changes arising from damage to medial temporal lobe during long preclinical stage of AD. The mean age of our subjects was 68.36 years suggesting that the participants have not yet reached the stage of declining weight which may commence with increasing amyloid accumulation at any stage later. There was no significant difference in regional uptakes of 18 F-AV-1451 between the groups. Recently a small study found increased amyloid deposition in elderly patients with MCI and OSA in correlation with oxygen desaturation index [21]. Such a correlation was not found in cognitively normal individuals with OSA [21], but the sample sizes of this study were very small, eight patients with normal cognitive function and five patients with MCI. Our subjects were elderly without an existing diagnosis of MCI. Interaction between sleep apnea and APOE ␧4 The mechanism through which OSA is associated with dementia and A␤ deposits is not precisely known. A␤ binding to APOE ␧4 results in A␤APOE ␧4 complex which is internalized by Very 8 A. Elias et al. / Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome [13] ACKNOWLEDGMENTS The study was supported by U.S. Department of Defense and Piramal Pharmaceuticals. Authors’ disclosures available online (https:// www.j-alz.com/manuscript-disclosures/18-0640r1). [14] [15] [16] REFERENCES [17] [4] [5] [6] [7] [8] [9] dA [18] [19] [20] rre cte [3] co [2] Fratiglioni L, Grut M, Forsell Y, Viitanen M, Grafström M, Holmén K, Ericsson K, Bäckman L, Ahlbom A, Winblad B (1991) Prevalence of Alzheimer’s disease and other dementias in an elderly urban population: Relationship with age, sex, and education. Neurology 41, 1886-1892. Shoenberg BS, Kokmen E, Okazaki H (1987) Alzheimer’s disease and other dementing illnesses in a defined United States population: Incidence rates and clinical features. Ann Neurol 22, 724-772. Jorm AF (2005) Risk factors for Alzheimer’s disease. In Dementia, 3rd Edn, Burns A, O’Brien J, Ames D, eds. Hodder Arnold, Boca Raton. Launer LJ, Anderson K, Dewey ME, Letenneur L, Ott, A, Amaducci LA, Brayne C, Copeland JR, Dartigues JF, Kragh-Sorensen P, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A (1999) Rates and risk factors for dementia and Alzheimer’s disease: Results from EURODEM pooled analyses. Neurology 52, 78-84. Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I (2002) Risk factors for Alzheimer’s disease: A prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 56, 445-453. Kivipelto M, Ngandu T, Fratiglioni L Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A (2005) Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 62, 1556-1560. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux RH, Pericak-Vance MA, Risch N, van Dujin CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta-Analysis Consortium. JAMA 278, 1349-1356. Mayeux R, Sano M, Chen J, Tatemichi T, Stern Y (1991) Risk of dementia in first-degree relatives of patients with Alzheimer’s disease and related disorders. Arch Neurol 48, 269-73. Jorm AF, Jolley D (1998) The incidence of dementia: A meta-analysis. Neurology, 51, 728-733. Un [1] f [12] oo [11] Pr We identify an association between obstructive sleep apnea and increased A␤ deposition. However, the association with A␤ deposition was moderated by APOE ␧4 and BMI. Overall the study does not support a direct association between OSA and increased A␤ deposition. Likewise, an association between obstructive sleep apnea and increased tau retention was not established in this study. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82, 4245-4249. Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Wisniewski HM (1989) Accumulation of abnormally phosphorylated x precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477, 90-99. Sabri O, Seibyl J, Rowe C, Barthel H (2015) Beta-amyloid imaging with florbetaben. Clin Transal Imaging 3, 13-26. Lowe VJ, Curran G, Fang P, Liesinger AM, Josephs KA, Parisi JE, Kantarci K, Boeve BF, Pandey MK, Bruinsma T, Knopman DS, Jones DT, Petrucelli L, Cook CN, GraffRadford NR, Dickson DW, Petersen RC, Jack CR Jr, Murray ME (2016) An autoradiographic evaluation of AV-1451 Tau PET in dementia. Acta Neuropathol Commun 4, 58. Kryger MF, Roth T, Dement WC (editors) (2015) Principles and practice of sleep medicine. Expert Consult premium edition. Elsevier Saunders. Punjabi NM (2008) The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 5, 136-143. Peppard PE, Young T, Barnet JH Palta M, Hagen EW, Hla KM (2013) Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 177, 1006-1014. Hoch CC, Reynolds CF, Houck PR Houck PR, Berman SR, Stack JA (1986) Sleep-disordered breathing in normal and pathologic aging. J Clin Psychiatry 47, 499-503. Reynolds CF, Kupfer DJ, Taska LS Hoch CC, Sewitch DE, Restifo K, Spiker DG, Zimmer B, Marin RS, Nelson J, et al. (1985) Sleep apnea in Alzheimer’s dementia: Correlation with mental deterioration. J Clin Psychiatry 46, 257-261. Mander BA, Marks SM, Vogel JW, Rao V, Lu B, Saletin JM, Ancoli-Israel S, Jagust, WJ, Walker MP (2015) ␤amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci 18, 1051-1057. Osorio RS, Gumb T, Pirraglia T, Varga AW, Lu S, Lim J, Wohlleber ME, Ducca EL, Koushyk V, Glodzik L, Mosconi L, Ayappa I, Rapoport DM, de Leon MJ (2015) Sleep disordered breathing advances cognitive decline in the elderly. Neurology 84, 1964-1971. Spira AP, Yager C, Brandt J, Smith GS, Zhou Y, Mathur A, Kumar A, Braăić JR, Wong DF, Wu MN (2014) Objectively measured sleep and ␤-amyloid burden in older adults: A pilot study. SAGE Open Med 2, 2050312114546520. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ (1989) The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research. Psychiatry Res 28, 193-213. Scarlata S, Pedone C, Curcio G, Cortese L, Chiurco D, Fontana D, Calabrese M, Fusiello R, Abbruzzese G, Santangelo S, Zito A, Incalzi RA (2013) Pre-polysomnographic assessment using the Pittsburgh Sleep Quality Index questionnaire is not useful in identifying people at higher risk for obstructive sleep apnea J Med Screen 20, 220-226. Wechsler D (1987) Wechsler Memory Scale-Revised. The Psychological Corporation, San Antonio, TX. Wechsler D (1997) Wechsler Adult Intelligence Scale - Third Edition. The Psychological Corporation, San Antonio, TX. Butters, N, Granholm E, Salmon DP, Grant I, Wolfe J (1987) Episodic and semantic memory: A comparison of amnesic and demented patients. J Clin Exp Neuropsychol 9, 479-497. or [10] uth CONCLUSION [21] [22] [23] [24] [25] [26] 9 A. Elias et al. / Risk of Alzheimer’s Disease in Obstructive Sleep Apnea Syndrome [33] [34] [35] [36] [37] [38] [39] [44] oo f [43] Pr [42] or [32] [41] uth [31] impairment and dementia in older women. JAMA 306, 613-619. Sharma RA, Varga AW, Bubu AM, Pirraglia E, Kam K, Parekh A, Wohlleber M, Miller MD, Andrade A, Lewis C, Tweardy S, Buj M, Yau PL, Sadda R, Mosconi L, Li Y, Butler T, Glodzik L, Fieremans E, Babb JS, Blennow K, Zetterberg H, Lu SE, Badia SG, Romero S, Rosenzweig I, Gosselin N, Jean-Louis G, Rapoport DM, de Leon MJ, Ayappa I, Osorio RS (2017) Obstructive sleep apnoea severity affects amyloid burden in cognitively normal elderly: A longitudinal study. Am J Respir Crit Care Med 197, 933-943. Vidoni ED, Townley RA, Honea RA, Burns JM (2011) Alzheimer’s Disease Neuroimaging Initiative. Alzheimer disease biomarkers are associated with body mass index. Neurology 77, 1913-1920. Hsu DC, Mormino EC, Schultz AP, Amariglio RE, Donovan NJ, Rentz DM, Johnson KA, Sperling RA, Marshall GA Harvard Aging Brain Study (2016) Lower late-life body-mass index is associated with higher cortical amyloid burden in clinically normal elderly. J Alzheimers Dis 53, 1097-1105. Kivimaki M, Luukkonen R, Batty GD, Ferrie JE, Pentti J, Nyberg ST, Shipley MJ, Alfredsson L, Fransson EI, Goldberg M, Knutsson A, Koskenvuo M, Kuosma E, Nordin M, Suominen SB, Theorell T, Vuoksimaa E, Westerholm P, Westerlund H, Zins M, Kivipelto M, Vahtera J, Kaprio J, Singh-Manoux A, Jokela M (2018) Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals. Alzheimer Dement 14, 601-609. Deane R1, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 118, 4002-4013. Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy GM Jr, Mignot E (2001) Association between apolipoprotein E epsilon4 and sleep disordered breathing in adults. JAMA 285, 2888-2890. Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T (2004) APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: The Sleep Heart Health Study. Neurology 63, 664-668. Lemoine P, Sassolas A, Lestra C, Laforest L, Chamba G (2004) Is there an interaction between sleep-disordered breathing, depression and apolipoprotein E phenotype? L’Encephale 30, 360-362. Thakre TP, Mamtani MR, Kulkarni H (2009) Lack of association of the APOE epsilon 4 allele with the risk of obstructive sleep apnea: Meta-analysis and meta-regression. Sleep 32, 1507-1511. Ancoli-Israel S, Kripke DF, Ancoli-Israel S, Klauber MR, Mason WJ, Fell R, Kaplan O (1991) Sleep-Disordered Breathing in community-dwelling elderly. Sleep 14, 486-495. dA [30] [40] [45] rre cte [29] co [28] Rey A, Osterrieth PA (1993) Translations of excerpts from Rey’s ‘Psychological Examination of Traumatic Encephalopathy’ and Osterrieth’s ‘The Complex Figure Test’. Clin Neuropsychol 7, 2-21. Reitan RM (1958) Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 8, 271-276. Zhou L, Salvado O, Dore V, Bourgeat P, Raning P, Macaulay SL, Ames D, Masters CL, Ellis KA, Villemagne VL, Rowe CC, Fripp J, AIBL Research Group (2014) MR-Less surface-based amyloid assessment based on 11 C PiB PET. PLoS 9, e84777. Bourgeat P, Villemagne VL, Dore V, Brown B, Macaulay SL, Martins R, Masters CL, Ames D, Ellis K, Rowe CC, Salvado O, Fripp J, AIBL Research Group (2015) Comparison of MR-Less PiB SUVR quantification methods Neurobiol Aging 36, S159-166. Cosentino FII, Bosco P, Drago V, Prestianni G, Lanuzza B, Iero I, Tripodi M, Spada RS, Toscano G, Caraci F, Ferri R. (2008) The APOE ␧4 allele increases the risk of impaired spatial working memory in obstructive sleep apnea. Sleep Med 9, 831-839. Mazza S, Pepin JL, Naëgelé B, Plante J, Deschaux C, Lévy P (2005) Most obstructive sleep apnoea patients exhibit vigilance and attention deficits on an extended battery of tests. Eur Respir J 25, 75-80. Naegele B, Launois SH, Mazza S, Feuerstein C, Pepin JL, Levy P (2006) Which memory processes are affected in patients with obstructive sleep apnea? Sleep 29, 533-544. Kilpinen R, Saunamaki T, Jehkonen M (2014) Information processing speed in obstructive sleep apnea syndrome: A review. Acta Neurol Scand 129, 209-218. Felver-Gant JC, Bruce AS, Zimmerman M, Sweet LH, Milmman RP, Aloia MS (2007) Working memory in obstructive sleep apnea: Construct validity and treatment affects. J Clin Sleep Med 6, 589-594. Andreou G, Vlachos F, Makanikas K (2012) Neurocognitive Deficits in Patients with Obstructive Sleep Apnea Syndrome (OSAS), Neuroscience, Dr. Thomas Heinbockel (Ed.), ISBN: 978-95351-0617-3, In Tech, Available from: http://www.intechopen.com/books/neuroscience/ neurocognitive-deficits-inpatients-with-obstructive-sleepapnea-syndrome-osas. Alchanatis M, Zias N, Deligiorgis N, Liappas I, Chroneou A, Soldatos C, Roussos C (2008) Comparison of cognitive performance among different age groups in patients with obstructive sleep apnea. Sleep Breath 12, 17-24. Naegele B, Pepin JL, Levy P, Bonnet C, Pellat J, Feuerstein C (1998) Cognitive executive dysfunction in patients with obstructive sleep apnea syndrome (OSAS) after CPAP treatment. Sleep 21, 392-397. Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S, Stone KL (2011) Sleepdisordered breathing, hypoxia, and risk of mild cognitive Un [27] [46] [47] [48] [49]