Relationship Between TMEM106B Polymorphism And The Pathogenesis Of Alzheimer’s Disease And Its Mechanism

Background:With the further intensification of aging,dementia has become one of the major diseases affecting all mankind,and Alzheimer’s disease（AD）is the most common cause of dementia.It is becoming more and more clear that lysosomes play an important role in the occurrence and development of AD.Studies on lysosomal molecular mechanisms and therapeutic targets have mushroomed.In recent years,researchers have found that the lysosome transmembrane protein gene TMEM106B affects the disease risk of AD,and its single nucleotide polymorphism（SNP）rs1990622 can regulate its expression.Previous studies have found that rs1990622 is associated with TDP-43 and hippocampal sclerosis pathology.in neuropathologically confirmed AD.Moreover,there was a significant correlation between rs1990622 and neurofilament light chain（Nf L）from cerebrospinal fluid（CSF）,a marker in the axon-damaged of AD and volume of left-sided temporal lobe in the general population.However,the relationship between rs1990622 and CSF,and neuroimaging phenotypes of AD is not clear.Therefore,our objective was to investigate whether rs1990622 is correlated with CSF and neuroimaging phenotypes of AD.Method:A total of 686 subjects who underwent TMEM106B rs1990622 genotyping,AD-related neurobiological and neuroimaging assessments were included from the Alzheimer’s Disease Neuroimaging Initiative（ADNI）CSFβ-amyloid(Aβ_1-42),phosphorylated tau（P-tau）,total tau（T-tau）and neuroimaging fluorine-18-labeled fluorodeoxyglucose positron emission computed tomography（FDG-PET）,the volume of hippocampus,entorhinal cortex and medial temporal lobe represent AD pathology.Multifactor linear regression model was used to analyze the association between rs1990622 and baseline AD CSF and neuroimaging phenotypes.Result:TMEM106B rs1990622 polymorphism was significantly correlated with the levels of CSF Aβ_1-42.Specifically,rs1990622 was significantly associated with Aβ_1-42levels in the total population（β=0.08,P<0.01）.No correlation was found between rs1990622 and FDG-PET SUV,hippocampus,entorhinal cortex and medial temporal lobe（β=0.011～137.2,P>0.05）.In the cognitive normality（CN）group,rs1990622 was significantly associated with FDG-PET SUV（β=0.024,P<0.05）.The results in the AD dementia population were consistent with the main analysis:rs1990622 was significantly associated with Aβ_1-42（β=0.143,P<0.01）.According to Aβ_1-42,308 subjects divided into AD pathological group and non-AD pathological group.rs1990622 was significantly associated with Aβ_1-42in AD pathological group（β=30.479,P<0.05）,and the association was more significant in AD dementia group（β=72.327,P<0.01）.In addition,in AD dementia group,rs1990622 also was significantly associated with FDG-PET SUV（β=0.043,P<0.05）.No similar correlation was observed in the non-AD group（β=39.191,0.009;P>0.05）.Further stratified analysis according to 234subjects with AD pathology showed that rs1990622 was significantly associated with Aβ_1-42in the female group（β=58.637,P<0.001）.Conclusion:In conclusion,our study showed that the polymorphism of the lysosomal membrane Protein gene TMEM106B rs1990622 is associated with the levels of CSF Aβ_1-42.The results of this study provide the basis for the possible molecular mechanism of TMEM106B in the pathological process of the natural history of AD.This study implies that it is crucial to figure out the function and role of TMEM106B in the investigation of molecular mechanism of AD in the future.