PLXNA4 Genotypes With Alzheime’s Disease Biomarkers

Background:The Plexin-A 4（PLXNA4）gene,has recently been identified in genome wide association studies（GWAS）,as a novel genetic player associated with Alzheimer’s disease（AD）.Additionally,PLXNA4 genetic variations were also found to increase AD risk by tau pathology in vitro.However,the potential roles of PLXNA4variants in the amyloid-β（Aβ）pathologywere not evaluated.objective:We investigated the effects of PLXNA4 loci on AD specific biomarkers（CSFproteins,glucose and Aβmetabolisms,brain structures）to explore the role of PLXNA4 in AD pathogenesis.Method:Five targeted loci capturing the top common variationsin PLXNA4,were extracted using tagger methods.Multiple linear regression modelswere used to explore whether these variations can affect the cerebrospinal fluid（CSF）(Aβ_1-42,T-tau,and P-tau)and neuroimaging phenotypes in the Alzheimer’s disease Neuroimaging Initiative（ADNI）dataset.Results:We detected that two loci（rs6467431,rs67468325）were significantlyassociated with CSF Aβ_1-42 levels in the hybrid population（rs6467431:P=0.01376,rs67468325:P=0.006536）and the significance remained after false discovery rate（FDR）correction（rs6467431:Pc=0.03441,rs67468325:Pc=0.03268）.In thesubgroup analysis,we further confirmed the association of rs6467431in the cognitivelynormal（CN）subgroup（P=0.01904,Pc=0.04761）.Furthermore,rs6467431-Acarriers and rs67468325-G carriers showed higher CSF Aβ_1-42 levels than non-carriers.Nevertheless,we did not detect any significant relationships between the levels of T-tau,P-tau and these PLXNA4 loci.In addition,we found that the rs156676-A allele and the rs78036292-G allele were significantly associated with the smaller baseline volume of precuneus and the larger baseline volume of middle temporalin All subjects,respectively.At one year of follow-up,we found that the rs6467431-G allele was significantly associated with the faster rate of atrophy of the left hippocampus in the hybrid population.After two years of follow-up,We found that threePLXNA4 loci（rs1863015,rs6467431,rs67468325）were strongly related to atrophy ofhippocampus,parahippocampusand middle temporal lobeon MRI.The results of the subgroup analysis further confirmed the above results.Moreover,rs78036292 were associated with Aβdeposition on AV45-PET imaging in CN,at baseline;rs67468325 were also associated with theglucose metabolism in right angularon FDG-PET in CN,at two years of follow-up.Conclusion:Our findings provided preliminary evidence that PLXNA4 variants can confer AD risk through modulating the Aβdeposition.Additionally,PLXNA4contributes to the risk of AD by altering neural degeneration biomarkers（glucose metabolism,brain atrophy）.