| Objective: Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are both common aging-related diseases.Numerous epidemiological studies have suggested that diabetes may accelerate the progression of AD through mechanisms such as acute and chronic hyperglycaemia,microangiopathy and insulin resistance.However,the relevance of fasting blood glucose(FBG)to the main pathological changes of AD is still unclear.Therefore,we aimed to explore the relationship between FBG and AD pathological biomarkers in the non-demented people without diabetes.Methods: 1,158 non-demented participants without diabetes from the Alzheimer’s Disease Neuroimaging Initiative(ADNI)database were included in this study,and 506 of them participated in longitudinal follow-up.All participants received measurements of FBG levels,cerebrospinal fluid(CSF)amyloid-β(Aβ)42,phosphorylated tau(P-tau)and total tau protein(T-tau)at baseline.Participants were divided into four groups according to fasting glucose levels: hypoglycaemic group(FBG < 3.9 mmol/L),normoglycaemic group(3.9 mmol/L ≤ FBG < 6.1 mmol/L),group with impaired fasting glucose(6.1 mmol/L ≤FBG < 7 mmol/L)and group with a provisional diagnosis of diabetes(FBG ≥ 7 mmol/L,only FBG levels met the diagnostic criteria for diabetes without typical symptoms and without a diagnosis of diabetes).We applied multiple linear regression models to examine the cross-sectional relationship between FBG levels and AD CSF core biomarkers.Interaction analysis were conducted to examine the possible moderating effects of age,gender,and APOE ε4 carriage status,subgroup analyses were then performed for the identified associations.In addition,the linear mixed-effects model was used to examine the relationship between FBG levels and longitudinal changes of AD CSF biomarkers.Besides,1266 non-demented participants from the CABLE were enrolled as a validation cohort to validate the positive association between FBG levels and CSF tau-related markers using the multiple linear regression model.Results: In ADNI cohort,we found that CSF T-tau(H = 14.927,p = 0.003)and P-tau(H =13.032,p = 0.005)levels were significantly higher in the provisional diagnosis of diabetes group than in the other three groups.However,hypoglycemic,normoglycemic,impaired fasting glucose and provisionally diagnosed diabetes groups had no statistical differences in age,gender,education,APOE ε4 carriage status,Mini-Mental State Examination(MMSE)scale,BMI and Aβ42 levels.Cross-sectional analysis showed that FBG levels were significantly positively correlated with T-tau(β = 0.124,p = 0.001)and P-tau(β =0.113,p = 0.003),but not with Aβ42(β = 0.067,p = 0.144).Linear mixed-effects models showed that higher FBG levels were associated with more longitudinal accumulation of Ttau(β<0.001,p=0.025)and P-tau(β<0.001,p=0.014),but not with longitudinal changes in Aβ42.Subgroup analysis revealed positive associations between FBG levels and CSF Ttau(β=0.118,p=0.004)and P-tau(β =0.110,p=0.007)in older adults over 65 years old.In APOE ε4 carriers,FBG levels were similarly positively associated with T-tau(β=0.160,p=0.012)and P-tau(β=0.154,p=0.017).When grouped by gender,FBG levels were significantly positively associated with T-tau(β=0.119,p=0.002)and P-tau(β =0.129,p=0.024)in females,whereas only positively associated with T-tau(β =0.101,p=0.047)in males.In CABLE cohort,we found similar positive correlation between FBG levels and CSF T-tau(β = 0.103,p = 0.020),P-tau(β = 0.089,p = 0.046).Conclusions and Significance: Our results found that higher FBG levels are associated with elevated cerebrospinal fluid tau-related biomarkers and were influenced by gender,age and APOE ε4 carriage status.It suggested that neurodegenerative effects of hyperglycaemia may be driven by pathways that promote neuronal tau accumulation,and controlling blood glucose attenuates abnormal tau protein aggregation,which may provide new lifestyle and dietary guidelines for the prevention of AD. |
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