The Study On The Relationship And Mechanisms Between Sleep Characteristics And Cognitive Function Among Older Adults

Part 1.Associations Between Sleep Characteristics and Dementia among Older Adults:a Population-based Cross-sectional StudyObjective:Sleep problems and dementia are both increasingly common as people age,and certain sleep characteristics of older adults may be related to a higher likelihood of dementia.However,previous cross-sectional studies on the relationship between sleep characteristics and dementia and its subtypes have rarely been conducted among older adults living in the rural communities.The certain sleep characteristics associated with dementia are poorly defined and whether their associations vary by demographics and apolipoprotein E(APDE)genotype among older adults are unclear.Thus,we sought to examine the associations of sleep characteristics with dementia and global cognitive function among rural-dwelling Chinese older adults,and to explore whether the associations varied by demographic factors and APOE genotype.Methods:This population-based cross-sectional study included 4742 rural-dwelling participants(age ≥65 years,57.1%women)from the Multimodal Interventions to Delay Dementia and Disability in Rural China(MIND-China).We used Pittsburgh Sleep Quality Index(PSQI)and Epworth Sleepiness Scale(ESS)to assess sleep characteristics such as sleep duration,sleep quality,sleep efficiency,sleep latency,and excessive daytime sleepiness.Global cognitive function was assessed with the Mini-Mental State Examination(MMSE).Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition(DSM-IV),criteria,and Alzheimer’s disease(AD)was further diagnosed according to the National Institute on Aging-Alzheimer’s Association(NIA-AA)criteria for probable AD.Data were analysed using binary logistic and general linear regression models.Results:Of the 4742 participants,173(3.6%)were diagnosed with dementia,including 115(2.4%)with AD.In the binary logistic regression model,multivariable-adjusted odds ratio(OR)of dementia was 1.71(95%CI,1.07-2.72)for very short sleep duration(≤4 hours vs.>6-8 hours),1.63(1.05-2.55)for>8 hours/night,1.11(1.03-1.20)for lower sleep efficiency(per 10%decrease),and 1.85(1.19-2.89)for excessive daytime sleepiness.Very short sleep duration,lower sleep efficiency,and excessive daytime sleepiness were significantly associated with being diagnosed with AD(multivariable-adjusted OR range:1.12-2.07;p<0.05).The associations of sleep problems with dementia and AD were evident mainly among young-old adults(<75 years)or APOE ε4 carriers.Among dementia-free participants,these sleep characteristics were significantly associated with worse global cognitive function.Conclusions:Sleep characteristics such as very short and long sleep duration,low sleep efficiency,and excessive daytime sleepiness are independently associated with an increased likelihood of dementia and poor global cognitive performance in Chinese rural older adults,in which the associations may vary by age and APOE ε4 status.Part 2.Associations Between Sleep Characteristics and Dementia among Older Adults:a Population-based Cohort StudyObjective:Changes in sleep characteristics may occur before the onset of dementia,suggesting that some sleep problems may be risk factors for dementia.In the Part 1,we have detected that certain sleep problems have a cross-sectional relationship with dementia and worse global cognitive function among rural-dwelling older adults,in which the associations may vary by age and APOE ε4 status.However,the longitudinal associations of sleep characteristics with the risk of dementia and cognitive decline,and whether their associations vary by demographics and APOE genotype among rural-dwelling older adults remain unclear.Investigating the longitudinal associations between sleep characteristics and the risk of dementia is helpful to identify the modifiable risk factors of dementia and to carry out early intervention,and to screen the people at high risk of dementia for regular monitoring of cognitive function.Therefore,we sought to examine the longitudinal associations of sleep characteristics with dementia and global cognitive decline among rural-dwelling Chinese older adults,and to explore whether the longitudinal associations varied by demographic factors and APOE genotype.Methods:This population-based cohort study included 1982 rural-dwelling dementia-free participants(age≥60 years,59.6%women)from the Shandong Yanggu Study of Aging and Dementia(SYS-AD).At the baseline(2014)and follow-up(2018)examinations,we used the PSQI and ESS to assess sleep characteristics such as sleep duration,time in bed,bedtime,rise time,mid-sleep time,sleep quality,sleep efficiency,sleep latency,and excessive daytime sleepiness.Cognitive function at baseline and follow-up was measured using the MMSE.Dementia was diagnosed following the DSM-IV criteria,and AD was further diagnosed according to the NIA-AA criteria for probable AD.Data were analysed using restricted cubic splines,Cox proportional-hazards models,general linear regression models,and Fine-Gray subdistribution hazard models.Results:During the mean follow-up of 3.7 years,dementia was diagnosed in 97(4.9%)participants,including 68(3.4%)with AD.Restricted cubic spline curves showed J-shaped associations of baseline sleep duration,time in bed,and rise time with dementia risk,and a reverse J-shaped association of mid-sleep time with dementia.In the Cox proportionalhazards models,when sleep parameters were categorized into tertiles,the multivariableadjusted hazard ratio(HR)of incident dementia was 1.69(95%CI 1.01-2.83)for baseline sleep duration>8 hours(vs.7-8 hours),2.17(1.22-3.87)for bedtime before 9PM(vs.10PM or later),and 2.00(1.23-3.24)for mid-sleep time before 1AM(vs.1-1.5AM).Long time in bed(>9 hours vs.8-9 hours)showed marginally significant association with dementia risk(HR[95%CI]=1.53[0.95-2.48],p=0.082).Early bedtime and mid-sleep time at baseline were significantly associated with incident AD(HR range:2.25-2.51;p<0.05).General linear regression models showed that,among individuals who were free of dementia at follow-up,baseline long time in bed,early bedtime and mid-sleep time,early and late rise time,and prolonged time in bed and advanced bedtime and mid-sleep time from baseline to follow-up were associated with greater global cognitive decline(p<0.05).These associations with global cognitive decline were statistically evident mainly among young-old adults(<75 years)or men.Conclusions:Sleep characteristics such as long time in bed,early bedtime and mid-sleep time are associated with an increased risk of dementia and AD,and the associations with greater cognitive decline are evident only among young-old adults(<75 years)or men.This suggests that cognitive function should be monitored in older adults who report prolonged time in bed and advanced bedtime,especially in older individuals aged<75 years and men.Future intervention studies may help clarify whether moderately reducing time in bed and delaying sleep timing can slow down cognitive decline and delay dementia onset in older adults.Part 3 Mechanisms Between Sleep Characteristics and Cognitive Function among Older AdultsObjective:In the Part 1 and Part 2,we have found that some sleep characteristics have crosssectional and longitudinal associations with dementia.Changes in sleep characteristics may occur in the early stage of the dementing process.Therefore,identifying specific sleep characteristics may help to identify older adults with increased risk of dementia.Mild cognitive impairment(MCI)defines an intermediate stage between normal aging and dementia,and people with MCI have an increased risk of developing into clinical stage of dementia.However,previous studies on the relationship of sleep characteristics with MCI and MCI subtypes have been scarcely conducted among rural-dwelling older adults,and the associations between various sleep characteristics and specific cognitive domains remain unclear.In addition,the mechanisms linking sleep problems and cognitive impairment remain unclear.It has been hypothesized that neurodegeneration and microvascular changes may mediate the relationship between sleep problems and cognitive impairment in a review,while population-based studies support this hypothesis remain sparse.Thus,we sought to examine the associations of sleep characteristics with MCI,MCI subtypes,and cognitive domains performance among rural-dwelling Chinese older adults,and to explore the role of neuroimaging markers of neurodegeneration and cerebral microvascular lesions in this relationship.Methods:This population-based cross-sectional study included 4477 rural-dwelling dementia-free participants(age≥65 years,56.2%women)from the MIND-China Study.We used the PSQI and ESS to assess sleep characteristics such as sleep duration,time in bed,bedtime,rise time,sleep quality,sleep efficiency,sleep latency,and excessive daytime sleepiness.Cognitive domains(i.e.,memory,verbal fluency,attention,and executive function)and global cognitive function were assessed using integrated neuropsychological assessments,and z-scores were calculated.MCI was diagnosed following the Petersen’s criteria.In the subsample(n=1004),3.0T brain magnetic resonance imaging(MRI)scans were performed,and then quantified markers of neurodegeneration(total brain tissue volume,grey matter volume,and white matter volume),and markers of microvascular lesions(total white matter hyperintensity[WMH]volume,periventricular WMH volume,and deep WMH volume).Data were analysed using restricted cubic splines,binary and multinomial logistic regression models,general linear regression models,and mediation models.Results:Of the 4477 participants,1203(26.9%)were diagnosed with MCI,including 1017(22.7%)with amnestic MCI and 186(4.2%)with non-amnestic MCI.Restricted cubic spline curves showed a J-shaped association between sleep duration and MCI after controlling for various confounders.Binary and multinomial logistic regression models showed that,after controlling for various confounders,long sleep duration(>8 hours vs.>6-8 hours),longer time in bed,earlier bedtime,later rise time,lower sleep efficiency,worse sleep quality,and daytime sleepiness were significantly associated with an increased likelihood of MCI(OR range:1.06-1.37;p<0.05)and amnestic MCI(OR range:1.07-1.38;p<0.05),except that the associations between sleep quality and MCI was marginally significant(OR[95%CI]=1.06[0.99-1.14],p=0.110).Earlier bedtime was associated with non-amnestic MCI,OR(95%CI)=1.30(1.09-1.56).For the associations between sleep characteristics and performance of cognitive domains,the associations of above sleep characteristics with global cognition and memory tended to be stronger than that with verbal fluency,attention,and executive function.In the MRI subsample,lower sleep efficiency,worse sleep quality or daytime sleepiness were associated with smaller total brain tissue volume and white matter volume,and greater total white matter hyperintensity(WMH)volume and periventricular WMH volume(multivariable-adjusted β coefficient range:-4.99-0.06,p<0.05),which were neuroimaging markers of neurodegeneration and microvascular lesions.Mediation analysis revealed that the relationship between lower sleep efficiency and worse memory function was partially mediated by WMH,with the proportion of mediation varying from 11.0%(total WMH)to 12.8%(periventricular WMH).Periventricular WMH mediated 13.1%of the relationship between worse sleep quality and worse memory function.Moreover,white matter atrophy mediated 10.1%of the relationship between lower sleep efficiency and worse attention performance.Conclusions:Sleep problems are clinical markers of prodromal dementia.Sleep characteristics such as long sleep duration and time in bed,early bedtime,late rise time,low sleep efficiency,poor sleep quality,and daytime sleepiness are associated with an increased likelihood of MCI,especially amnestic MCI subtype,and poor global cognitive function and memory function.Sleep problems and cognitive impairment may be linked via common neuropathologies of cerebral microvascular lesions and neurodegeneration.