| Objectives:As the most common type of senile dementia,Alzheimer's disease?AD?is a progressive neurological degenerative disease.At present,the pathogeny and pathogenesis of AD have not been clarified very well.So far,many studies have proved that AD is characterized by the presence of extracellular deposits of the amyloid-??A??and intracellular twisted strands of the tau protein.Therefore,it has been the focus of research in this field that using genetic methods to explore susceptible genes,studying epigenetic modifications to regulate its expression.The Genome-wide association study?GWAS?verified more than a dozen candidate genes associated with AD,providing a new path for further research.Recently,lots of articles have verified that several genes in the triggering receptor expressed on myeloid cell?TREM?gene cluster are associated with the pathogenesis of AD.Among them,TREM2 is particularly concerned as an AD risk gene.The lack of TREM2 is associated with reduced bacterial clearance and increased proinflammatory cytokine production,thus indicating its anti-inflammatory and protective functions.Currently,TREML1?also known as TLT-1?has been shown to antagonize the proinflammatory activation of TREM1 by competing with TREM1 ligands.Based on this,it can be speculated that the TREML1 gene has a potential association with the pathogenesis of AD.Rs9357347 located at the TREM gene cluster could increase TREM2and TREML1 brain gene expression,which is considered as the potential mechanism for protection from Alzheimer's disease?AD?.To investigate the role of rs9357347 in AD pathogenesis,we explored the effects of rs9357347 on AD specific biomarkers in AD,MCI and CN subjects.Methods:This study analyzed the association of rs9357347 with AD-related cerebrospinal fluid?CSF?and neuroimaging markers from 201 cognitively normal?CN?older adults,349 individuals with mild cognitive impairment?MCI?,and 172 individuals with AD dementia from the Alzheimer's Disease Neuroimaging Initiative?ADNI?.We next analyzed the association in 259 amyloid-?abnormal?A?+?elders and 117 amyloid-? normal?A?-?elders(A?+:CSF A?1-42?192pg/ml;A?-:CSF A?1-42>192pg/ml).Associations between diagnosis and demographic,clinical factors were tested at baseline.We examined differences in continuous variables?education years,age,volume,etc.?and categorical data?gender,APOE?4 status?using Kruskal–Wallis test and chi-square test respectively.The correlations between rs9357347 and various endophenotypes?CSF proteins,MRI and FDG-PET?were estimated using linear regression models at baseline.Furthermore,association between rs9357347 and the above phenotypes in the longitudinal study were tested using linear mixed-effects models.Of note,we chosen the4-year follow-up data for all three existing genotypes to make analysis.All outcome variables in linear regression models and linear mixed-effects models were standardized to z scores to facilitate comparisons between genotypes.Difference with a P-value<0.05was accepted to be statistically significant.All regression analyses were corrected for age,APOE?4 genotype,gender and educational level,and the regression analysis of brain structure volume was also corrected for intracranial volume.All statistical analyses were performed by R3.4.0.Results:First of all,demographic and clinical characteristics at the baseline were summarized.Among the three clinical groups?AD,MCI,CN?,Gender,education level,volume of brain structure,FDG and the frequency of the APOE?4 allele were found to be correlated with diagnosis.But the diagnosis did not differ by age.Individuals in AD and MCI cohorts exhibited typical CSF biomarker phenotype of AD with elevated mean levels of T-tau and P-tau181 and lower level of A?1-42.Then,we found that rs9357347 had association with CSF A?1-42 in CN group??=0.357,P=0.009?at baseline.In AD group,rs9357347 was associated with total tau?T-tau?level??=-0.436,P=0.007?.Moreover,the strong influence made by rs9357347 on T-tau was also seen in A?+group??=-0.202,P=0.036?.In the longitudinal study,rs9357347 was also found to be associated with A?1-42 in CN group??=0.329,P=0.023?.In AD group,the mutation of rs9357347 was associated with slower accumulation of T-tau??=-0.472,P=0.002?and P-tau 181??=-0.330,P=0.019?.Furthermore,the obvious influence made by rs9357347on T-tau was also seen in A?+group??=-0.241,P=0.013?.Conclusions and Relevance:This study supported that rs9357347 reduced the risk of AD by modulating both amyloid-?pathology and neuronal degeneration.It indirectly reflected the mechanism through which TREM2 and TREML1 modify AD risk.The completion of this project will not only enrich and improve the pathogenesis of AD,but also provide new targets and theoretical basis for early warning,diagnosis,treatment and drug development of AD. |
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