| Objective: CRecently,chronic non-communicable diseases,represented by type 2 diabetes mellitus(T2DM),cerebrovascular diseases(CBD)and dementia have become a global public health and social problems.We aimed 1)to estimate the incidence of CBD and dementia during 1998-2016,2)to examine the association between T2 DM and CBD subtypes,3)to explore assess the relationship between the single and combined impact effect of T2 DM and CBD on dementia risk,to assess the role of taking genetic and early-life familial environmental factors in these associations into account,and to exploreinvestigate whether and to what extent CBD mediates the risk of T2DM-dementia related toassociation T2 DM.Methods: Participants were members derived from of the nationwide Swedish Twin Registry(STR),which was started in the 1960 s.Within the STR,44919(43238 CBD-free andor 44275 dementia-free)twin individuals aged ≥40 who participated in the Screening across the Lifespan Twin Study were followed up for 16 years.Data on emographic and lifestyle factors were collected following a standard protocal.Information on T2 DM,CBD and dementia diagnoses was obtained from the National Patient Registry.Data were analyzed as following: 1)standarzed cumulative incidence and incidence density of CBD and dementia the follow-up period were estimated on the basis of total number of incident cases adjusted for age and sex;2)generalized estimating equation(GEE)models was used for classical(unmatched)case-control study design to examine the association between T2 DM and subtypes of CBD as well as their relation to dementia.3)conditional logistic regression was used in co-twin matched case-control analyses in CBD/dementia-discordant twin pairs.Logistic regression was used to test the difference in ORs from unmatched case-control analysis vs.co-twin matched case-control analysis and to explore the role of genetic and early-life familial environmental factors in the T2DM-CBD,T2DM-dementia and CBD-dementia associations;and 4)structural equation modeling(SEM)was performed to investigate the mediating effect of CBD on dementia related to T2 DM.Results:(1)During the follow-up,among the 43530 CBD-free individuals,the cumulative incidence and incidence density of CBD were 11.43% and 7.1/1000 person-years,respectively,higher in men,and increased with age.The standarzed incidence and incidence density of CBD are 0.77% and 7.9/1000 person-years.During the follow-up,among the 44789 individuals,the cumulative incidence and incidence density of dementia were 7.50% and 4.6/1000 person-years,respectively,higher in women,and increased with age.The standarzed incidence and incidence density of dementia are 0.30% and 2.8/1000 person-years.(2)Association between T2 DM and CBD: In multi-adjusted GEE models,those with T2 DM had significantly higher ORs of ischemic CBD(OR=1.48,95% CI: 1.35-1.61),including cerebral infarction(OR=1.61,95% CI: 1.46-1.79)and occlusion of cerebral arteries(OR=1.98,95% CI: 1.30-3.01)than T2DM-free participants,but not transient ischemic attack.The associations of T2 DM with subarachnoid hemorrhage(OR=1.27,95% CI: 0.76-2.11)and intracerebral hemorrhage(OR 1.11;95% CI 0.87-1.41)were not significant.In the co-twin matched case-control analysis,the association between T2 DM and cerebral infarction was attenuated(OR 1.49;95% CI: 1.19-1.86).The difference in ORs from the GEE models based on unmatched case-control analyses vs.co-twin control analyses was statistically significant.(3)Association between T2 DM and dementia: In multi-adjusted GEE models,T2 DM was associated the risk of dementia(OR=1.14,95% CI: 1.03-1.27).In the co-twin matched case-control analysis,the association between T2 DM and dementia was attenuated(OR 1.49;95% CI: 1.19-1.86).The difference in ORs from the GEE models based on unmatched case-control analyses vs.co-twin control analyses was statistically significant.Association between CBD and dementia: In multi-adjusted GEE models,those with TIA(OR=1.42,95% CI: 1.19-1.86),cerebral infarction(OR=1.43,95% CI: 1.28-1.61),intracerebral hemorrhage(OR=1.42,95% CI: 1.10-1.82)had significantly higher ORs of ischemic CBD.The associations of T2 DM with subarachnoid hemorrhage(OR=1.08,95% CI: 0.67-1.75)and occlusion of cerebral arteries(OR=1.11,95% CI: 0.82-1.51)were not significant.In the co-twin matched case-control analysis,the association between cerebral infarction and dementia became non-significant(OR=1.23,95% CI: 0.96-1.56).The difference in ORs from the GEE models based on unmatched case-control analyses vs.co-twin control analyses in monozygotic twins was statistically significant.There was no interaction of T2 DM and cerebral infarction on the dementia risk.In mediation analysis,cerebral infarction mediated approximately 18% of the total association between T2 DM and dementia.Conclusions: During the follow-up period,the standarzed incidence and incidence density of CBD in Swedish middle-aged and older twin individuals are are 0.77% and 7.9/1000 person-years.The standarzed incidence and incidence density of dementia are 0.30% and 2.8/1000 person-years.T2 DM increases the risk of cerebral infarction and occlusion of cerebral arteriesas well as dementia,and TIA,cerebral infarction and intracerebral hemorrhage in turn is associated with the risk of dementia.Genetic and early-life familial environmental factors may contribute to the association of T2 DM with cerebral infarction/dementia.Cerebral infarction may mediate one fifth of the association between T2 DM and dementia. |
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