Omics‐derived biological modules reflect metabolic brain changes in Alzheimer's disease

Abstract

AbstractINTRODUCTIONBrain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([18F]FDG‐PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive.METHODSHere, we integrated [18F]FDG‐PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel‐wise linear regression analysis.RESULTSOur results showed that multiple transcriptomic modules are associated with brain [18F]FDG‐PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak‐t(223) = 4.86, P value < 0.001) and zinc‐finger–related regulatory units (peak‐t(223) = 3.90, P value < 0.001).DISCUSSIONBy integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity–associated genes and zinc‐finger–related regulatory units are highly associated with brain metabolic changes in AD.Highlights We conducted an integrated analysis of system‐based transcriptomics and fluorodeoxyglucose positron emission tomography ([18F]FDG‐PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [18F]FDG‐PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [18F]FDG‐PET. Zinc‐finger transcription factor targets were associated with AD brain [18F]FDG‐PET metabolism.