Elucidating Circadian and Sleep Phenotypes and Relation to Cognitive Impairment in Alzheimer`s Dementia

Introduction: Although sleep disruption in Alzheimer’s disease (AD) pathogenesis has been described, the role of circadian rhythm dysfunc- tion (CRD) is less understood. We hypothesize greater CRD and sleep disruption with poorer cognitive function in AD compared to normal cognition.

Methods: We examined 3 groups:1)mild cognitive impairment with positive AD biomarkers(MCI-AD),n=18, 2)cognitively normal at high risk for AD(HR)(APOEƐ4 carriers),n=19, 3)cognitively normal APOEƐ4 non-carriers(CL),n=16 (National Institute of Aging, IMMUNE-AD). DNA extraction and APOEƐ4 genotyping were performed under the Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank. We evalu- ated actigraphy-based (Motionlogger MicroWatch, Ambulatory Monitoring,Inc®) sleep (wake episodes(WE), total sleep time(TST), sleep efficiency(SE), sleep fragmentation index(SFI)) and circadian (mesor, amplitude, robustness, sleep regulatory index(SRI), intradaily stability) predictors and sleep study-based (ApneaLink Air by ResMed®) predictors (apnea hypopnea index(AHI,3% desaturation) and recording time<90%SaO2) across the groups and assessed associ- ation with cognition (Mini-Mental State Exam(MMSE)). Analysis of variance (ANOVA) or Kruskal-Wallis with Bonferroni adjustment was used for cross-group comparisons. ANCOVA assessed cross-group as- sociation of MMSE and sleep/circadian indices. Models were adjusted for age, sex, race, education, and BMI.

Results: Age differed across MCI-AD, HR, and CL groups (68.4±6.2,71.2±3.7,73.7±3.7 respectively,p=0.008). MCI-AD had more WE than HR and CL (14.4±5.6,10.9±3.9,10.9±3.5 respectively,p=0.033). In MCI-AD, the following associations were observed: 5% increase in SE was associated with 0.49 point higher MMSE (coefficient0.49, 95%CI[0.03,0.95],p=0.038), 1 hour in- crease in TST was associated with 0.81 point higher MMSE (coeffi- cient0.81, 95%CI[0.24,1.37],p=0.006), and 1 unit increase in SFI was associated with 0.36 point lower MMSE (coefficient-0.36, 95%CI[- 0.64,-0.08],p=0.013). Key measures differed: CLs had lower AHI, MCI-AD had less TST SaO2<90%, MCI-AD had the largest and HR the lowest SFI, and MCI-AD had lesser robustness but higher mesor and amplitude.

Conclusion: In this comparative study of carefully AD biomarker- phenotyped and APOEƐ4-genotyped patients and normal cognition controls, less sleep time and more fragmented sleep are associated with poorer MMSE scores in MCI-AD. Preliminary results show cog- nitively normal participants at risk of AD(HR) do not show CRD seen in MCI-AD and are more consistent with controls (CL).

Support (if any): Catalyst Award. MCI cohort: Alzheimer’s Association, 2014‐NIRG‐305310. IMMUNE-AD, R01AG022304. CADRC, P30 AG062428. Jane and Lee Seidman Fund.