Effects Of PICALM Rs3851179 Polymorphism On The Default Mode Network Function In Mild Cognitive Impairment

Objective Phosphatidylinositol-binding clathrin assembly protein(PICALM)rs3851179 has been associated with Alzheimer's disease(AD);in particular,the A allele may serve a protective role,while the G allele serves as a strong genetic risk factor.Therefore,the identification of genetic polymorphisms associated with the default mode network(DMN)is required in subjects of mild cognitive impairment(MCI).The aims of this study,therefore,were as follows:(i)to determine whether altered functional patterns of the DMN are associated with the PICALM rs3851179 polymorphism in subjects with MCI and(ii)whether there is an association between the effects of PICALM on the functional connectivity(FC)of the DMN and cognitive function.Methods In all,32 MCI subjects and 32 healthy controls(HCs)underwent resting-state functional magnetic resonance imaging(rs-fMRI)and a genetic imaging approach.Subjects were divided into four groups according to the diagnosis(i.e.,MCI and HCs)and the PICALM rs3851179 polymorphism(i.e.,AA/AG genotype and GG genotype).The differences in FC within the DMN between the four subgroups were explored.The posterior cingulated cortex(PCC)hub [coordinate in the MNI space:-2,-45,34] was selected to generate a 6-mm radius spherical seed region,followed by coregistration to the functional data.To explore the FC changes that cannot be attributed to anatomical difference,the voxel's likelihood of containing grey matter were introduced as nuisance variables.The Mann Whitney U test and ?2 tests(only for gender)were performed to explore the differences in demographic data and neuropsychological performances.Within groups: to determine the patterns of DMN in each of four groups,the spatial maps of DMN IC in each group were submitted to a random-effect analysis using one-sample t-tests.Between groups: Similar to previous investigations,the genotype-by-disease interactions were performed by the general linear model.The effects of age,gender and education were corrected.Post hoc tests were performed to explore the different DMN patterns of regions with genotype-by-disease interaction among four groups.ANOVA analyses followed by the least-significant difference(LSD)analyses were utilized.To explore the cognitive significances of the genotype-by-disease interaction in DMN,the spearman correlation analyses were performed between the Z-transformed FC strengths and the neuropsychological performances.The SPSS 22.0 software was used and the statistical significance was set at P < 0.05.Results The MCI subjects showed significant worse performances in general cognition(i.e.MMSE),episodic memory(i.e.AVLT-20 min DR and CFT-20 min DR),information processing speed(i.e.DSST and TMT-A)and executive function(i.e.TMT-B and VFT).However,the MCIs and HCs showed comparable performances of visuospatial function(i.e.CDT and CFT).The main effects of disease were detected in the left superior/ middle temporal gyrus(LSTG/MTG)and right inferior parietal lobule(RIPL),while the main effects of genotype were observed in the right inferior frontal gyrus(RIFG)and bilateral superior frontal gyrus(BSFG).Further,the regions associated with genotype-by-disease interactions were the left middle temporal gyrus(LMTG)and the left medial frontal gyrus(LMFG).These changes in LMFG FC were generally manifested as an ?inverse U-shaped curve?,while a ?U-shaped curve? was associated with the LMTG FC between these four subgroups(all P < 0.05).For MCIs,the higher FC within the LMFG was related to better performance of information processing(i.e.,TMT-A,rho =-0.503,P = 0.047)in the subgroup of patients with the AA/AG genotype,while episodic memory was positively related to the FC within LMFG for patients with GG genotype(i.e.,AVLT 20 min DR,rho = 0.72,P = 0.044).Conclusions The PICALM rs3851179 gene polymorphism significantly affects DMN network of MCI,but the mode of action in different brain regions are not the same,such as the LMFG and LMTP may have the opposite effect mode.The FC of the site is positively proportional to the speed of episodic memory and information processing,which indicates that the FC of LMFG is closely related to cognitive function.Subjects with the GG genotype were more prone to episodic memory impairment than those with the AA/AG genotype,which was more likely to lead to the occurrence of AD.