Integration Of Multiple Genetic Polymorphisms Into The Genetic-imaging Analyses For Subjects With Mild Cognitive Impairment

Part one: The associations between the genetic risk score and default mode network trajectory during Alzheimer's disease processBackground: Longitudinal changes in the default mode network (DMN) are used to monitor the progression of Alzheimer's disease (AD) and to distinguish mild cognitive impairment (MCI) subjects who are more likely to develop AD. The genetic basis causing the different trajectory should be explored to illustrate AD pathology.Methods: Averagely 35-month follow-ups were performed in 87 MCI subjects and 131 healthy controls (HCs), and they had the genetic risk scores (GRS) based on the top 11 AD-related loci. We studied DMN differences between MCIs and HCs at baseline and the corresponding behavioral significance. The differential longitudinal changes in DMN among HCs, stable MCIs (SMCls) and MCI-to-AD converters were examined, and gene-based associations were performed to explore whether these single nucleotide polymorphisms (SNPs) caused DMN deterioration.Results: The converters showed more functional connectivity (FC) longitudinal decreases of DMN within the left medial prefrontal gyrus, bilateral inferior parietal lobes (IPLs) and right parahippocampal gyrus/hippocampus than the HCs and SMCIs.The associations were detected at risky alleles and FC declines in all AD spectra.Interestingly, the influence of APOE s4 varied as the disease progressed; APOE s4 was associated with longitudinal FC decreases only for HCs in the single SNP-based analyses and deteriorated DMN integration in the SMCIs by combining the effects of other loci. However, the GRS without APOE ?4 predicted FC decline for converters.Conclusions: The functional disconnection developed in the early stage of AD, and it correlated with the AD severity. MCI subjestcs take advantage of neural function within prefrontal-parietal brain to keep the relatively normal cognition. The maintenance of the functional compensation partially determined the disease process of MCI patients. The AD-related DMN changes partially resulted from the AD-related risky SNP. Integration of multilocus genetic risk predicted the longitudinal trajectory of DMN and may be used as a clinical strategy to track AD progression.Part two: Brain insulin resistance deteriorates cognition by altering the topological features of brain networksBackground: Insulin resistance represents one of the mechanisms underlying the link between type 2 diabetes (T2D) and Alzheimer's disease (AD). We explored its in vivo neurobiology based on pathway-based genetic association analyses.Methods: Eighty-seven mild cognitive impairment (MCIs) subjects and 135 matched controls (HCs) were employed at baseline, and they underwent functional MRI scans,clinical evaluations and exon sequencings of 20 genes related to brain insulin resistance. A longitudinal study for an average of 35 months was performed to assess their cognitive decline over time.Results: By using cognition as the phenotype, we detected genes that modified cognitive impairments, including AKT2, PIK3CB, IGF1R, PIK3CD, MTOR, IDE,AKT1S1 and AKT1. Based on these loci, the mass univariate modeling was utilized to construct the functional network. The MCIs showed disconnections mainly in the cerebellum-frontal-temporal regions, while compensations may occur in frontal-parietal regions to maintain the overall network efficiency. Moreover, the behavioral significance of the network was highlighted, as topological characteristics of the medial temporal lobe and the prefrontal cortex partially determine longitudinal cognitive decline.Conclusions: The brain insulin resistance modify the cognitive performance in early stage of AD, and the influences partially result from the connectivity changes of the brain topological network. The prefrontal and hippocampal nodes represent the targeted regions of insulin disorder, and the topological characteristics within these regions predicted the disease progress for MCI subjects. Moreover, our results suggested the restoration of insulin activity represents a promising therapeutic target for alleviating cognitive decline associated with T2D and AD.