Mild cognitive impairment (MCI) is a transition between normal cognition (NC) and Alzheimer’s disease (AD). Differences in cortical thickness (ΔCT) have been reported in cases that degenerate from MCI to AD. The aspects of genetic and transcriptional variation related to ΔCT are vague. In this study, using an 8-year longitudinal follow-up outcome, we investigated the genetic correlates of ΔCT in MCI subjects with degeneration from MCI to AD (MCI_AD). We employed partial least squares regression (PLSR) on brain T1-weighted magnetic resonance imaging (MRI) images of 180 participants [143 stable MCI (MCI_S) participants and 37 MCI_AD participants] and brain gene expression data from the Allen Institute for Brain Science (AIBS) database to investigate genes associated with ΔCT. We found that upregulated PLS component 1 ΔCT-related genes were enriched in chemical synaptic transmission. To verify the robustness and specificity of the results, we conducted PLSR analysis invalidation and specificity datasets and performed weighted gene co-expression network analysis instead of PLSR for the above three datasets. We also used gene expression data in the brain prefrontal cortex from the Gene Expression Omnibus (GEO) database to indirectly validate the robustness and specificity of our results. We conclude that transcriptionally upregulated genes involved in chemical synaptic transmission are strongly related to global ΔCT in MCI patients who experience degeneration from MCI to AD.

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