Effects Of CD33 Variants On Neuroimaging Biomarkers In Nondemented Elders

Background: Two common variants(rs3826656 and rs3865444)in CD33 have been verified to be related to Alzheimer's disease(AD).Our study examined the impacts of the two AD-related CD33 common variants on neuroimaging biomarkers in nondemented elders and in distinct diagnostic groups stratified by pathological status.Methods: In our study,we recruited 1082 non-demented elders from the Alzheimer's Disease Neuroimaging Initiative(ADNI)database,including 375 cognitively normal(CN)population and 707 mild cognitive impairment(MCI)patients at baseline.Participants were grouped into A?-positive(N = 462)and A?-negative groups(N = 322)according to the level of A? measured in cerebrospinal fluid(CSF)or on AV45-PET.In A?-positive group,CN subjects were defined as preclinical AD(N = 119),and MCI subjects were defined as prodromal AD(N = 343).We chose hippocampal volume,amygdala volume,parahippocampal volume,middle temporal volume,entorhinal cortex thickness and total brain volume(TBV)as regions of interest(ROIs)according to their important role in predicting AD risk and progression.At baseline,we evaluated the associations between CD33 common variants(rs3826656 and rs3865444)and the volumes of ROIs using linear regression models.In the longitudinal study,we tested the associations of the two CD33 variants with the four-year atrophy rates in ROIs using linear mixed-effects models.All analyses were conducted in the total non-demented elderly population,A?-positive group(including preclinical AD and prodromal AD groups)and A?-negative group.Results: In the total non-demented elderly population,the results of cross-sectional study indicated that rs3826656 was associated with the volumes of right hippocampus(P = 0.0062)and amygdala(Amygdala-L: P = 0.0089;Amygdala-R: P = 0.0239),while rs3865444 was associated with right middle temporal volume(P = 0.0495).The results of longitudinal study showed that rs3826656 was associated with atrophy rates of right hippocampus(P = 0.0072),amygdala(Amygdala-L: P = 0.0085;Amygdala-R: P = 0.0107),parahippocampus(Parahippocampus-L: P = 0.0101;Parahippocampus-R: P = 0.0413)and right entorhinal(P = 0.0336),while rs3865444 was related to right middle temporal atrophy rate(P = 0.0170)during four-year follow-up.However,all these associations in the total non-demented elderly population failed to achieve significant levels after FDR correction.Subgroup analyses showed that rs3826656 was associated with hippocampal and amygdala volumes in A?-positive group(Hippocampus-R: P = 0.0001,Pc = 0.0022;Amygdala-L: P = 0.0002,Pc = 0.0044;Amygdala-R: P = 0.0003,PC = 0.0066)and prodromal AD group(Hippocampus-R: P = 0.0001,Pc = 0.0022;Amygdala-L: P = 0.0001,Pc = 0.0022;Amygdala-R: P = 0.0004,Pc = 0.0088),while rs3865444 was related to right entorhinal volume in A?-positive group(P = 0.0013,Pc = 0.0286)and prodromal AD group(P = 0.0369).The results of longitudinal study in subgroups showed similar findings that rs3826656 was associated with atrophy rates of hippocampus and amygdala in A?-positive group(Hippocampus-R: P = 0.0001,Pc = 0.0022;Amygdala-L: P = 0.0001,Pc = 0.0022;Amygdala-R: P = 0.0001,Pc = 0.0022;Hippocampus-L: P = 0.0016,Pc = 0.0352)and prodromal AD group(Hippocampus-R: P = 0.0005,Pc = 0.0110;Amygdala-L: P = 0.0003,Pc = 0.0066;Amygdala-R: P = 0.0003,Pc = 0.0066),while rs3865444 was related to right entorhinal atrophy rate in A?-positive group(P = 0.0013,Pc = 0.0286)and in prodromal AD group(P = 0.0186).However,the association of rs3865444 with right entorhinal volume and atrophy rate in prodromal AD group failed to achieve significant levels after FDR correction.No associations were found between the two CD33 variants and neuroimaging biomarkers in A?-negative and preclinical AD group after FDR correction.Conclusions: These results suggested that the two CD33 common variants(rs3826656 and rs3865444)influenced volumes and atrophy rates of AD-related brain regions in nondemented elders.Subgroup analyses showed that the effects mainly existed in A?-positive group instead of A?-negative group,and the effects have started from prodromal AD stage.