Abstract
Background:Previous studies showed no obvious symptoms but subtle structural brain changes in a long preclinical stage of Alzheimer's disease (AD), then localized cortical and sub-cortical atrophy in MCI, and spread aggressively to nearly whole brain neurodegeneration in AD. However, the neurobiological and pathogenic substrates underlying these structural changes across AD spectrum remain largely understood.Methods: We obtained structural MRI imaging from ADNI datasets, including 83 early-stage mild cognitive impairments (EMCI), 83 late-stage mild cognitive impairments (LMCI), 83 AD, and 83 normal controls (NC), and aimed to explore structural changes across the full clinical AD spectrum and their genetic mechanism. Partial least square regressions and Spearman correlations were performed to explore how these changes associated with gene expression level obtained from Allen Human Brain Atlas. Finally, functional enrichment analyses were conducted using Metascape analysis to explore ontological pathways of the consistent genes. Results:We identified significant volume atrophy in left thalamus, left cerebellum, and bilateral middle frontal gyrus across AD spectrum. These structural changes were positively associated with gene expression levels of ABCA7, SORCS1, SORL1, PILRA, PFDN1, PLXNA4, TRIP4, and CD2AP, whereas were negatively associated with gene expression levels of CD33, PLCG2, APOE, and ECHDC3 for all three groups. Moreover, these results were verified in sub-groups of converted and stable EMCI and LMCI. Further gene enrichment analyses revealed that these positively associated genes were mainly involved in positive regulation of cellular protein localization and negative regulation of cellular component organization, whereas the negatively associated genes were mainly involved in positive regulation of iron transport. Conclusions:Overall, these results suggested that structural changes in prodromal and clinical AD might result from interaction of the same gene lists, which offered a better understanding of biological mechanisms underlying structural changes in prodromal and clinical AD.