The Association Of Lifespan Cognitive Reserve Indicator With Mild Cognitive Impairment And Dementia-a Cohort Study

Objective: The term cognitive reserve(CR)has been proposed as a compensatory mechanism to cope with age-related brain damage and to account for inter-individual variability in the ability to delay the incidence of dementia in the presence of brain pathologies.CR is an active construct,which develops from continued life experiences such as education,cognitive or social activities.So far,CR was mostly assessed by single indicator,evidence on whether and to what extent lifespan CR accumulation may reduce dementia or mild cognitive impairment(MCI)risk is still limited,and the role of brain pathology in the association is unclear.We aimed to verify the hypothesis that high lifespan CR accumulation is associated with a reduced risk of dementia or MCI and delay the progression from MCI to dementia,and to estimate the role of brain pathology in the association.Methods: The study was based on the Memory and Aging Project(MAP),an ongoing community-based cohort study.Beginning in 1997 through 2018,a total of 2155 participants were enrolled.At the baseline,all participants underwent a comprehensive assessment,including social demographic characteristics and life style such as education,early-,mid-and late-life cognitive activities,social activity in late life and social network in late life which were used to assess lifespan CR.At the baseline and thereafter,participants underwent a comprehensive clinical assessment,including medical history,neurological examination,and detailed cognitive function testing such as dementia or MCI.During the follow-up period,about 80% participants died and underwent autopsy and neuropathologic evaluations.Structural equation modeling(SEM)was performed to capture lifespan CR;Cox regression models or competing risks model was used to estimate the association between lifespan CR and dementia or MCI;Logistic regression or linear regression model was used to estimate the association between lifespan CR and brain pathology.Results:(1)Among 2155 participants [mean age 80.0(SD)7.6] years old),115(5.3%)had dementia and 546(25.34%)had MCI.During the follow-up,among 2040 participants without demetia,the incidence of dementia and MCI were 41.1/1000 and the 90.5/1000 person-years,respectively,and the standardized incidence of them were 19.7/1000 person-years and 59.3/1000 person-years.The incidence of MCI /dementia increased with age.(2)The final CR indicator was generated based on the best-fitting SEM with the five CR-enhancing factors including education,early-,midand late-life cognitive activities,and social activities in late life.High lifespan CR indicator was associated with a reduced risk of dementia(Hazard Ratio,HR=0.93,95% CI:0.88-0.97),and the risk of dementia was reduce by 35%(HR=0.65,95% CI:0.49-0.84)for the participants with highest lifespan CR indicator compared to that with the lowest lifespan CR indicator.In autopsied participants,lifespan CR was not related to most brain pathologies except for gross infarcts(Odds Ratio,OR=0.52,95% CI:0.33-0.81)and the CR-dementia association remained significant after additional adjustment for brain pathologies.Highest lifespan CR indicator was associated with a reduced dementia risk even among participants with high Alzheimer's disease pathology,and any infarcts.(3)High lifespan CR indicator was associated with a reduced risk of MCI(HR=0.95,95% CI:0.92-0.98)and delayed its progression to dementia(HR=0.92,95% CI:0.86-0.99).The risk of MCI(HR=0.73,95% CI:0.59-0.91)and its progression to dementia(HR=0.65,95% CI:0.43-0.95)was reduce by 27% and 35%,respectively,for the participants with highest lifespan CR indicator compared to that with the lowest lifespan CR indicator.In autopsied participants,lifespan CR was not related to most brain pathologies except for gross infarcts(OR=0.47,95% CI:0.27-0.79)or microinfarcts(OR=0.40,95% CI:0.17-0.96),and the association of lifespan CR indicator with MCI and its progression to dementia remained significant after additional adjustment for brain pathologies.Highest lifespan CR indicator delayed the progreesion from MCI to dementia even among participants with any gross infarcts.Conclusions: The incidence of dementia and MCI increase with age.Lifespan high CR indicator reduces the risk of dementia and MCI,and delays the progression from MCI to dementia,independently of brain pathology,even in the presence of high Alzheimer's disease(AD)burden or infarcts.