Faculty Bibliography

Increasing evidence links cognitive-decline and Alzheimer's disease (AD) to various sleep disorders, including obstructive sleep apnea (OSA). With increasing age, there are substantial differences in OSA's prevalence, associated comorbidities and phenotypic presentation. An important question for sleep and AD researchers is whether OSA's heterogeneity results in varying cognitive-outcomes in older-adults compared to middle-aged adults. In this review, we systematically integrated research examining OSA and cognition, mild cognitive-impairment (MCI) and AD/AD biomarkers; including the effects of continuous positive airway pressure (CPAP) treatment, particularly focusing on characterizing the heterogeneity of OSA and its cognitive-outcomes. Broadly, in middle-aged adults, OSA is often associated with mild impairment in attention, memory and executive function. In older-adults, OSA is not associated with any particular pattern of cognitive-impairment at cross-section; however, OSA is associated with the development of MCI or AD with symptomatic patients who have a higher likelihood of associated disturbed sleep/cognitive-impairment driving these findings. CPAP treatment may be effective in improving cognition in OSA patients with AD. Recent trends demonstrate links between OSA and AD-biomarkers of neurodegeneration across all age-groups. These distinct patterns provide the foundation for envisioning better characterization of OSA and the need for more sensitive/novel sleep-dependent cognitive assessments to assess OSA-related cognitive-impairment.

STUDY OBJECTIVES/OBJECTIVE:To determine the effect of self-reported clinical diagnosis of Obstructive Sleep Apnea (OSA) on longitudinal changes in brain amyloid-PET and CSF-biomarkers (Aβ42, T-tau and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI) and Alzheimer's Disease (AD) elderly. METHODS:Longitudinal study with mean follow-up time of 2.52±0.51 years. Data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI and 325 AD elderly. Main Outcomes were annual rate-of-change in brain amyloid-burden (i.e. longitudinal increases in florbetapir-PET uptake or decreases in CSF-Aβ42 levels); and tau-protein aggregation (i.e. longitudinal increases in CSF total-tau (T-tau) and phosphorylated-tau (P-tau)). Adjusted multi-level mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate-of-biomarker-change differed between participants with and without OSA. RESULTS:In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B=.06, 95% CI .02, .11 and B=.08, 95% CI .05, .12 respectively) and decrease in CSF-Aβ42 levels (B=-2.71, 95% CI -3.11, -2.35 and B=-2.62, 95% CI -3.23, -2.03, respectively); as well as increases in CSF T-tau (B=3.68, 95% CI 3.31, 4.07 and B=2.21, 95% CI 1.58, 2.86, respectively) and P-tau (B=1.221, 95% CI, 1.02, 1.42 and, B=1.74, 95% CI 1.22, 2.27, respectively); compared to OSA- participants. No significant variations in the biomarker changes over time were seen in the AD group. CONCLUSIONS:In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

Introduction: We determined whether Obstructive Sleep Apnea (OSA) and beta-Amyloid Burden (Abeta) act additively or synergistically to promote conversion from cognitive normal (CN) to mild cognitive impairment (MCI) and from MCI to AD.
Method(s): In this longitudinal observational study, we examined CN (n=298) and MCI (n=418) older adults from the ADNI database (adni.loni.usc.edu). OSA was self-reported during a clinical interview. Brain Abeta was assessed using Florbetapir-PET imaging. The primary outcome of the analysis was conversion from CN to MCI (CN participants) and from MCI to AD (MCI participants). Participants were required to have a baseline and at least one follow-up clinical visit that identified their cognitive status. Logistic mixed-effects models with random intercept and slope were used to assess associations between OSA, Abeta, and risk of conversion from CN to MCI, and MCI to AD. All models included age at baseline, sex, APOE4 status, years of education, and their interactions with time.
Result(s): Of the 716 participants, 329 (46%) were women. The overall mean (SD) age was 74.7 (5.0) years, and the overall mean (SD) follow-up time was 5.5 (1.7) years (Range: 2.7 - 10.9 years). In CN participants at baseline, conversion to MCI was associated with both OSA (beta = 0.418; 95% CI, 0.133 to 0.703; P < .001) and higher Abeta-burden (beta = 0.554; 95% CI, 0.215 to 0.892; P < .001). The interaction of OSA and Abeta burden with time was significant (beta = 1.169, 95% CI, 0.776 to 1.562; P < .001), suggesting a synergistic effect. In MCI participants at baseline, conversion to AD was associated with both OSA (beta = 0.637; 95% CI, 0.291 to 0.982; P < .001) and higher Abeta-burden (beta = 1.061; 95% CI, 0.625 to 1.497; P < .001). The interaction of OSA and Abeta burden with time was significant (beta = 1.312, 95% CI, 0.952 to 1.671; P < .001), suggesting a synergistic effect.
Conclusion(s): In both CN and MCI elderly, Abeta modified the risk of progression to AD in OSA participants. OSA patients maybe more physiologically susceptible as Abeta load becomes increasingly abnormal

Introduction: We determined whether the co-occurrence of OSA and hypertension interact synergistically to promote beta-Amyloid burden and cognitive decline in clinically normal older adults Methods: Prospective longitudinal study utilizing NYU cohort of community-dwelling cognitively-normal elderly, with baseline and at least one follow-up of CSF-Abeta42 (measured using ELISA), and neuropsychological visits. OSA was defined using AHI4%. Hypertension diagnosis was according to AHA-guidelines. Cognitive variables assessed included Logic-2, Animal-Fluency [AF], Vegetable-Fluency [VF]), Boston-Naming-Test [BNT], Digit-Symbol-Substitution-Test [DSST], Trails Making Test-A and B [TMT-A and B]). Linear mixed-effects models with random intercept and slope were used to assess associations between OSA, hypertension, and longitudinal changes in CSF-Abeta and cognition, controlling for age-at-baseline, sex, APOE4-status, years-of-education, and their interactions with time.
Result(s): Of the 98 participants, 63 (64.3%) were women. The mean (SD) age was 69.6 (7.3) years and follow-up time was 2.46 (0.64) years. OSA and hypertension were each associated with faster rate-of-change in CSF-Abeta42 (beta = -3.11; 95%CI, -3.71, -2.51; and beta= -2.82, 95% CI -3.29, -2.35, P < .01 for both respectively). The interaction of OSA and hypertension with time was significant (beta= -1.28, 95% CI -1.78 to -0.78, P < .01) suggesting a synergistic effect. No significant associations were seen between annual-changes in CSF-Abeta42 and cognitive-decline. However, faster decline in VF, and DSST were associated with OSA (beta = -0.054; 95%CI, -0.094, -0.013; P = .02; beta = -0.058; 95%CI, -0.084, -0.033; P < .05 for both respectively), and with hypertension (beta = -0.048; 95%CI, -0.079, -0.017; P = .04; beta = -0.078; 95%CI, -0.098, -0.057; P = .002; respectively). The interaction of OSA and hypertension with time was significant for both VF and DSST (beta = -0.033, 95%CI, -0.048, -0.018; P < .001 and beta = -0.040, 95%CI, -0.064, -0.016; P < .001, respectively), suggesting a synergistic effect.
Conclusion(s): In cognitive-normal elderly OSA individuals, vascular risk may complement AD-biomarkers in assessing risk of prospective cognitive-decline in preclinical AD