Correlation Between TREML2 Gene Polymorphism And Neuroimaging Biomarkers Of Alzheimer's Disease

Objective: Alzheimer disease(AD)is a common neurodegenerative disease and the most common type of dementia in the elderly,with its typical pathological changes are intracellular tau neurofibrillary tangles and extracellular Amyloid-beta(A?)plaque deposition.The etiology of Alzheimer's disease is complex,and genetic factors are one of the main reasons.In recent years,with the improvement of genetic testing technology and the deepening of related research,it is generally suggested that genetic mutation plays a crucial role in the development of AD.To date,a large number of genes and sites have been proposed to be associated with the risk of late-onset Alzheimer's disease(LOAD).Recently,the International Genomics of Alzheimer's Project(IGAP)study found that the rs3747742 site of the TREML2 gene is a novel genome-wide locus associated with the risk of AD.TREML2 polymorphisms were associated with late-onset AD susceptibility in the Caucasian population,and this association was also confirmed in independent samples of Northern Han Chinese population.In his study,we aimed to detect the association of TREML2 missense mutations(rs3747742-C)with cerebrospinal fluid(CSF)AD-related proteins(including CSF A? and tau levels),neuroimaging data and cognition by using neuroimaging biomarkers and data from the ADNI(Alzheimer's Disease Neuroimaging Initiative,adni.loni.usc.edu)database.So we can further analyze the role of TREML2 rs3747742 in the pathogenesis of LOAD.Methods: In this study,a total of 1,306 subjects from the ADNI database,including 374 cognitively normal(CN),705 mild cognitive impairments(MCI)and 227 patients with Alzheimer's disease(AD)were included after strict quality control screening.To explore the association between TREML2 rs3747742 and the risk of AD,we used R software to analyze in additive genetic model and we extracted the data on corresponding cerebrospinal fluid(CSF)proteins,neuroimaging and cognitive function scale scores from ADNI database.We used Kruskal-Wallis rank sum test to examine the differences in clinical and demographic characteristics of participants included in our analysis.We performed a multiple linear regression model and a mixed-effects model to explore the associations of TREML2 genotypes with baseline and longitudinal variables respectively.All above analyses were adjusted for age,gender,education,APOE?4 status and cranial volume.Statistical significance was considered to have been achieved when P<0.05.Data analyses were performed using R version 3.4.1 statistical software.Results: After adjusting for age,gender,education level,APOE?4 status and cranial volume,we observed that both in total population and AD patients,subjects with C allele(CC,TC)had lower T-tau levels(?=-7.7764,P = 0.0143;?=-0.1548,P = 0.0096)than TT allele carriers at baseline.Furthermore,we also found that total subjects(?=-0.1548,P =0.0096)and AD patients(?=-0.3961,P =0.0115)with CC and TC genotypes showed a slower rate of change in CSF T-tau levels after adjusting for age,gender,education,APOE?4 status and cranial volume over a 4-year follow-up.However,no associations were found with CSF A? levels,P-tau levels,neuroimaging biomarkers and cognitive function neither for baseline variables nor for longitudinal data.Conclusion: In summary,our findings showed that TREML2 genetic mutation(rs3747742-C)was associated with CSF T-tau levels in AD patients,suggesting this mutation plays an important role in AD-related neurodegeneration.More independent researches with large sample size and diverse ethnicity are required to confirm the role of TREML2 in AD pathology.