Type 2 Diabetes Mellitus Polygenic Genetic Risk Score Predict The Conversion Of Amnestic Mild Cognitive Impairment To Alzheimer’s Disease

BackgroundAmnestic mild cognitive impairment（a MCI）is a cognitive deficit state with memory impairment as the main symptom.It is a type of syndrome between normal aging and Alzheimer’s disease（AD）and shows an extremely higher risk of developing into AD.There is evidence that about 12%of a MCI are annually convert to AD.Identifying risk factors that can predict conversion from a MCI to AD is clinically important for early interventions of AD.AD and Type 2 diabetes mellitus（T2DM）have similar neuropathological characteristics,and whether T2DM polygenic genetic risk can predict the conversion of a MCI to AD remains to be studied.ObjectiveHere,we aimed to investigate whether T2DM specific polygenic genetic risk can predict the conversion of a MCI to AD,and further explore the underlying neurological mechanism.Subjects and MethodsIn this study,all a MCI patients were from the Alzheimer’s disease Neuroimaging Initiative（ADNI）.According to the follow-up results in March 2019,a MCI subjects were divided into the conversion（a MCI-C,N=164）and the stable（a MCI-S,N=222）groups.Summary statistics data of the genome-wide association analysis of AD and T2DM were used as the discovery samples to calculate the polygenic risk scores（PRS）,including PRS_T2DM and PRS_AD,PRS_{s T2DM} and PRS_{s AD} were calculated after removing the coincident variants.Logistic regression,chi-square test,Cox proportional hazards regression,receiver operating characteristic curve（ROC curve）were used to explore the predictive efficacy of different PRSs on the conversion of a MCI to AD.We further explored the underlying neurological mechanism.We downloaded the high-resolution sagittal brain structure magnetic resonance images of 386 a MCI from ADNI.The voxel-wise morphological measurement（VBM）was performed to calculate the gray matter volume（GMV）of whole brain voxels using CAT12,and the surface-based morphology（SBM）was performed to calculate the thickness,surface area and volume of whole cerebral cortex using Freesufer.Using spm12 and QDEC software,a voxel-based general linear model analysis method was used to explore the brain regions related to PRS_{s T2DM}.We defined the brain region with the above correlation as a region of interest（ROI）,extracted brain structure indexes,and analyzed the correlation between these indexes with PRS_{s T2DM}.The mediation analysis was used to test the causal effect from PRS_{s T2DM} to brain to a MCI conversion.Results1.PRS_T2DM predicts conversion of a MCI to ADPRS_T2DM can predict a MCI convert to AD,and the explained variance is 3.74%.After removing the coincident variants of these two diseases,PRS_{s T2DM} can still independently predict the conversion of a MCI to AD,and the explained variance is3.93%.According to the PRS_T2DM of a MCI,we divided them into different risk groups.The conversion rate of the high risk group（50.78%）was significantly higher than that of the low risk group（34.20%）（χ²=10.86,P=0.001）;Compared to the high risk group,the middle（HRs=0.67,95%CI=0.46-0.97,P=0.034）and low risk group（HRs=0.60,95%CI=0.41-0.88,P=0.009）had 0.67 times and 0.60 times of risk for the a MCI-C.2.Correlativity between PRS_{s T2DM} and brain structureIn the a MCI-C group,PRS_{s T2DM} was significantly negatively correlated with gray matter volume on the right superior frontal gyrus（MNI coordinates:x=18,y=36,z=55.5;t=-3.97;458 voxels,Alpha Sim corrected,P_C<0.05）.In all a MCI patients,PRS_{s T2DM} was significantly negatively correlated with the cortex volume of the right superior occipital gyrus（cluster size:108.05mm³,CWP=0.0196,Monte Carlo simulation correction,CWP<0.05）.3.Mediation analysisMediation analysis demonstrated the causal interference from PRS_{s T2DM} to the cortex volume of the right superior occipital gyrus and the conversion of a MCI.ConclusionIn this study,it was found that T2DM specific polygenic genetic risk can predict the conversion of a MCI to AD,and the cortex volume of the right superior occipital gyrus may play an intermediary role in this conversion.