Association Of Obesity With Tau Pathology In Cognitively Normal Individuals

Objective: Midlife obesity is associated with an increased risk of Alzheimer’s disease(AD),while overweight or obesity in late life is associated with a decreased risk of AD.AD,is pathologically characterized by the accumulation of amyloid-β(Aβ)plaques and the aggregation of hyperphosphorylated tau,which could be measured by cerebrospinal fluid(CSF)Aβ,total-tau(T-tau),and phosphorylated tau(P-tau)levels.Body mass index(BMI),waist circumference(WC)and waist-to-height ratio(WHt R)are considered as obesity indexes,the relationships between these obesity indices and CSF biomarkers of AD pathology are needed to be clarified.This study aimed to investigate the associations of obesity types and obesity indices with CSF biomarker in different life stages,and to further explore the potential metabolic changes of AD pathological proteins that may be caused by obesity,thus providing early prevention for AD.Methods: We recruited 1051 cognitively normal individuals(61.94 ± 10.29 years old,59.66%men)from the Chinese Alzheimer’s Biomarker and Lifestyl E(CABLE)study.We detected the concentration of CSF Aβ42,T-tau and P-tau via enzyme-linked immunosorbent assay(ELISA),and used BMI,WC and WHt R as indirect obesity indices to determine the types of human obesity.Multivariate linear models were used to examine the relationships between obesity types or obesity indices and CSF biomarkers after adjusting for age,gender,education and apolipoprotein E(APOE)ε4 status.Sensitivity analyses were run by additionally adding lifestyle-related factors(smoking and alcohol drinking status),comorbidities(history of hypertension,diabetes,coronary heart disease,and stroke)and the levels of plasma lipids in the models to assess the robustness of results.Interaction analyses were run to estimate the possible moderating effects of age on the identified associations,the above studies were conducted and compared in the middle-aged and elderly populations,respectively.Results: In the total population,compared with normal controls,individuals with overweight and general obesity showed lower levels of CSF T-tau and CSF T-tau/Aβ42(p <0.05),central obesity was negatively associated with CSF T-tau levels(p < 0.05),but not with CSF T-tau/Aβ42 levels(p > 0.05);higher BMI was related to lower levels of CSF Ptau(p < 0.05).In late life,for the obese subtypes,the CSF T-tau level was lower in the overweight,general obesity,and central obesity groups compared with the normal control group(p < 0.05).As for the obesity indices,higher BMI was found to be associated with lower levels of CSF tau-related proteins,including CSF T-tau,CSF P-tau,and CSF Ttau/Aβ42(p < 0.05),and there were significant associations of WC or WHt R with CSF Ttau and CSF T-tau/Aβ42 levels(p < 0.05).The above-mentioned significant associations are still robust after relevant sensitivity analysis.In midlife,no similar significant associations were observed.Conclusion: Overall,our study proposed protective associations of general obesity or central obesity against tau pathology in late life.The robust relationships also existed between the obesity indices and lower load of tau pathology,indicating that late-life individuals with higher levels of obesity indices might be at a lower risk of developing AD,which further consolidates the beneficial effects of obesity in preventing AD in specific life stages.However,no association of midlife general obesity or central obesity with CSF AD biomarkers was found,suggesting midlife obesity and CSF AD biomarkers could act an independent role in the AD risk,respectively.Future longitudinal studies are necessarily required to scrutinize the changes of these obesity-related AD pathologies over time.