Association Between Plasma Apolipoprotein M And Alzheimer Disease

Objective:Alzheimer disease(AD)is an age-related neurodegenerative disease,characterized by progressive cognitive and social function impairment,and is the most important type of dementia in the elderly.With the acceleration of the aging process of the global population,the number of new cases of AD increasing rapidly at a rate of about 9.9 million per year,AD has already posed a serious threat to global public health.Although it is generally believed that AD is caused by a combination of age,genetics and environmental factors,the exact pathogenesis of AD has not yet been fully identified,and effective early diagnosis and disease-modifying treatments are lacking,which requires further research.Apolipoprotein M(ApoM)is a newly discovered apolipoprotein with a molecular weight of 26 kDa,which is mainly expressed in liver,kidney,adipose tissues and cerebrovascular endothelial cells of human beings.In plasma,ApoM is widely distributed in lipoproteins,the majority of which(approximately 95%)are binding with high density lipoprotein(HDL-C)and is critical in the formation of pre-β-HDL and cholesterol efflux.Beside binding to HDL-C,ApoM is also an important molecular chaperone of sphingosine-1-phosphate(SIP),which stably bound and transported SlP in the circulation and interstitial fluid,promoting the activation of SlP receptors(S1PRs)and forming an important signaling axis.Studies have shown that ApoM binds to SlP and activates S1PR1,thereby affecting the permeability of the blood-brain barrier(BBB),and that BBB permeability is increased in ApoM-deficient mice,implying that ApoM may play an important role in the transport of small molecules in the BBB.Whereas dysregulation of S1P signaling and disruption of the BBB are early events leading to many central nervous system disorders including AD.Furthermore,considerable evidence suggests a strong link between cholesterol homeostasis and AD,implying that genes associated with brain cholesterol homeostasis may be potential candidates for AD.In a recent genomic wide association study(GWAS),the apolipoprotein gene APOM was shown to be a major regulator of cellular cholesterol,driving lipid metabolic pathways and associated with risk of AD.A proteomic study has also shown that ApoM levels are significantly lower in the CSF of AD patients compared to controls.However,it is unclear whether plasma ApoM is a factor involved in the pathogenesis of AD.Therefore,this study aims to investigate the expression of ApoM and its derived indicators in the plasma of AD patients,its influence on the occurrence of AD,and its correlation with the main clinical features of AD and representative blood biomarkers.Further,we explored the efficacy of plasma ApoM and its derived indicators for the diagnosis of AD.The completion of these studies will contribute to a new perspective on the mechanisms of AD and provide new evidence for blood biomarkers of AD.Methods:1.A total of 67 AD patients and 73 age and sex matched cognitively normal controls(CN)hospitalized in the Department of Neurology of Sichuan Provincial People’s Hospital,Western Theater Command General Hospital and Chengdu Eighth People’s Hospital from March 2021 to September 2021 were included in this study.2.The cognitive function of all subjects was assessed by mini-Mental State Examination(MMSE)and Montreal Cognitive Assessment(MoCA).Activities of daily living(ADL)scale was used to evaluate the daily living ability of all the participants.The vascular factors were assessed by the Hachinski ischemic scale(HIS).Participants with abnormal cognitive function assessment were further assessed with the Clinical Dementia Rating(CDR)3.A comprehensive questionnaire,electronic medical record system and laboratory test management system were used to collect general demographic information,AD risk factors,medical history,part of the blood tests and APOE genotype.4.Plasma levels of ApoM,p-tau217,p-taul81 and neurofilament light chain(NfL)were determined using an enzyme-linked immunosorbent assay(ELISA).Furthermore,with the previous research experience of our team and in view of the close relationship between ApoM and lipids,we divided the plasma ApoM by the commonly used clinical lipid indicators to carry out the ratio[i.e.,the ratios of ApoM/total cholesterol(TC),ApoM/triglycerides(TG),ApoM/HDL-C and ApoM/low density lipoprotein cholesterol(LDL-C)]to find more optimal ApoM-related blood biomarkers.5.All statistical analyses were performed using IBM SPSS Statistics version 25 and Medcalc 15.2.2,GraphPad Prism 6.0 for graphing.Data were expressed as mean±standard deviation((?))or median and interquartile range(IQR),depending on the data distribution,and the Mann-Whitney U test or the t-test was used to test the differences between the two groups.Categorical variables were expressed as proportions,and a Chi-square test was applied in the comparison between groups.Correlations between the two variables were analyzed by performing Spearman’s rank correlation or Pearson’s correlation.Logistic regression was used to analyse the influence of plasma ApoM and its-derived indicators on the occurrence of AD,and the results were expressed as odds ratio(OR)with corresponding 95%confidence interval(CI).The area under curve(AUC)was calculated to assess the predictive power of ApoM and its-derived indicators on AD using single and multiple indicator combinations.Using the DeLong’s test,we compared the area under the curve(AUC)between ApoM with its-derived indicators,and between the basic model(sex,age,APOE ε4 and BMI)with basic model combined with ApoM and its-derived indicators,respectively.All tests were two-sided,and P<0.05 was considered significantly.Results:1.There were no statistical differences in age,sex,years of education,smoking and drinking history,hypertension and diabetes mellitus between the two groups(all P>0.05).Compared with the CN group,the proportion of APOE ε4 positive was significantly higher in the AD group(P<0.0001),while body mass index(BMI)(P<0.0001),TC(P=0.001),TG(P<0.0001)and HDL-C(P=0.001)were significantly decreased.2.MMSE scores and MoCA scores were significantly lower in the AD group than those in the CN group(both P<0.0001),while ADL scores were significantly higher in the CN group(P<0.0001).Plasma p-tau 217(P<0.0001),p-tau 181(P=0.001)and NfL(P<0.0001)were significantly higher than those in CN group.3.Compared with CN group,plasma ApoM,ApoM/TC,ApoM/TG,ApoM/HDL-C and ApoM/LDL-C were significantly increased(all P<0.0001).4.Plasma ApoM and most of its derived indicators were significantly negatively correlated with MMSE scores and MoCA scores,and significantly positively correlated with ADL scores.And plasma ApoM and most of its derived indicators were significantly and positively correlated with plasma p-tau217 and NfL levels,respectively.Similar correlations persisted in total participants and in subgroup analyses grouped according to APOE ε4 carriage status and gender.5.The associations of plasma ApoM and its-derived indicators with the presence of AD were investigated by multivariate logistic regression analysis.When AD risk factors(age,sex and APOE ε4 carriage status)and BMI were adjusted,the plasma ApoM(OR=1.058,95%CI:1.027-1.090,P<0.0001)and the ratios of ApoM/TC(OR=1.239,95%CI:1.120-1.372,P<0.0001),ApoM/TG(OR=1.064,95%CI:1.035-1.095,P<0.0001),ApoM/HDL-C(OR=1.069,95%CI:1.037-1.102,P<0.0001)and ApoM/LDL-C(OR=1.064,95%CI:1.023-1.106,P=0.002)were significantly associated with the presence of AD,respectively.6.The ROC analysis demonstrated that both plasma ApoM and its derived indicators had diagnostic value for AD,with an AUC range of(from 0.712 to 0.825,P<0.0001).In addition,the diagnostic model was conducted by combining plasma ApoM and its derived indicators with risk factors of AD,and the AUC range was(from 0.868 to 0.906,P<0.0001),which further improved the diagnostic efficacy of AD.Conclusion:1.Compared with the CN group,plasma ApoM and its derived indicators were significantly higher in AD patients,even after adjusting for AD risk factors such as age,gender and APOE ε4 carrier status,higher plasma ApoM and its derived indicators were still significantly associated with the occurrence of AD.These results suggest that there is a potential relationship between plasma ApoM and its derived indicators with AD.2.The plasma ApoM and its derived indicators were significantly negatively correlated with MMSE scores and MoCA scores,and significantly positively correlated with ADL scores.Also significantly positively correlated with plasma p-tau217 and NfL levels.This suggests that plasma ApoM and its derived indicators have the potential to reflect the degree of cognitive decline and neurological impairment in AD patients,and may have the potential to be candidates for new blood biomarkers of AD.3.Plasma ApoM and its derived indicators exhibit high diagnostic efficacy for AD,and constructing a combined diagnostic model with AD risk factors can further improve the diagnostic efficacy for AD.To sum up,the study preliminarily clarified the relationship between plasma ApoM and its derived indicators with AD.On the one hand,it suggests that ApoM may be involved in the pathogenesis of AD,on the other hand,it also suggests that ApoM,as an easily available blood indicator,may have the potential to become a blood biomarker of AD.In addition,the relationship and mechanism between ApoM and AD is worthy of further study in the future.