| Background:Microglia-mediated neuroinflammation plays a critical role in the pathogenic process of Alzheimer’s disease（AD）.CC-chemokine ligand 2（CCL2）and its receptors CCR2,the key immunomodulators for microglial activation,have been implicated in the pathogenesis of AD.The associations between CCL2/CCR2 single nucleotide polymorphisms（SNPs）and the risk of AD are still unclear.Therefore,the research aimed to explore the association of the CCL2/CCR2 variants with the pathological changes and cognitive decline of AD.Methods:A total of 486 participants were recruited from the Alzheimer’s disease Neuroimaging Initiative（ADNI）,among whom 198 were cognitively normal individuals,272 were mild cognitive impairments patients and 16 were AD patients.Genotype data of five SNPs（CCL2rs4586,CCL2 rs13900,CCR2 rs1799865,CCR2 rs1799864 and CCR2 rs3092960）were obtained from genome-wide association study and whole genome sequencing.Baseline and longitudinal amyloid beta（Aβ）and phosphorylated tau（P-tau）biomarkers in cerebrospinal fluid（CSF）,18F-Florbetapir and 18F-flortaucipir-positron emission tomography（PET）and cognitive assessments were extracted from the ADNI database.The effects of CCL2/CCR2genotypes on the baseline variables and pathological changes and cognitive decline of AD were assessed with linear regression model and linear mixed-effects model respectively.The effects of relevant genotypes on tau accumulation were further evaluated according to the Aβstatus so as to identify whether the effects were independent of Aβstatus.All above analyses were adjusted for age,gender,education,apolipoproteinε4 status and cognitive status.Statistical significance was considered to have been achieved when p<0.05.Results:1.At baseline,CCL2 rs4586-CC and CCR2 rs1799865-CC carriers exhibited higher CSF Aβ42 levels than those of TT/TC carriers（CCL2 rs4586,p=0.030;CCR2 rs1799865,p=0.023）.However,there were no differences in CSF Aβ42,CSF P-tau,Aβ-PET,tau-PET and cognition among other genotypes（p>0.05）.2.At follow-up,CCL2 rs4586-CC carriers exhibited a slower global Aβ-PET accumulation（β=-0.025,p=0.012）than those of TT/TC carriers.However,they exhibited a faster accumulation of CSF P-tau（β=0.023,p=0.035）and global tau-PET（β=0.100,p=0.014）.In addition,CCL2 rs13900-TT carriers exhibited a slower CSF Aβ42 decline than those of CC/TC carriers（β=-0.046,p=0.018）.CCR2 rs1799865-CC carriers exhibited a slower CSF P-tau accumulation（β=-0.033,p=0.033）and slower cognitive decline（β=0.101,p=0.007）than those of TT/TC carriers.However,neither CCR2 rs1799864-AA nor CCR2 rs3092960-AA was significantly associated with the pathological changes and cognitive decline.3.CCL2 rs4586-CC carriers exhibited a slower Aβ-PET accumulation particularly within stage I（β=-0.023,p=0.032）and stage II（β=-0.025,p=0.011）.They exhibited a faster accumulation of tau-PET especially in Braak I（β=0.128,p=0.034）,Braak III/IV（β=0.084,p=0.043）and the inferior temporal gyrus（β=0.094,p=0.025）.In addition,the congruent effects of CCL2 rs4586 on tau accumulation existed only in Aβ-group,as is shown in global tau-PET（β=0.153,p=0.031）and Braak I（β=0.198,p=0.039）.Conclusion:Our study revealed for the first-time that CCL2 rs4586-CC,CCL2 rs13900-TT and CCR2rs1799865-CC were associated with the pathological changes and cognitive decline of AD.CCL2/CCR2 variants may play a key role in cognitive decline of AD by modulating both Aβand tau pathology,which may offer potential therapeutic targets for AD treatment by targeting CCL2 and CCR2 protein. |
