Abstract
Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis. Previous studies of gene expression using bulk tissue samples often fail to consider changes in cell-type composition when comparing AD versus control, which can lead to differences in expression levels that are not due to transcriptional regulation. We mined five large transcriptomic AD datasets for conserved gene co-expression module, then analyzed differential expression and differential co-expression within the modules between AD samples and controls. We performed cell-type deconvolution analysis to determine whether the observed differential expression was due to changes in cell-type proportions in the samples or to transcriptional regulation. Our findings were validated using four additional datasets. We discovered that the increased expression of microglia modules in the AD samples can be explained by increased microglia proportions in the AD samples. In contrast, decreased expression and perturbed co-expression within neuron modules in the AD samples was likely due in part to altered regulation of neuronal pathways. Several transcription factors that are differentially expressed in AD might account for such altered gene regulation. Similarly, changes in gene expression and co-expression within astrocyte modules could be attributed to combined effects of astrogliosis and astrocyte gene activation. Gene expression in the astrocyte modules was also strongly correlated with clinicopathological biomarkers. Through this work, we demonstrated that combinatorial analysis can delineate the origins of transcriptomic changes in bulk tissue data and shed light on key genes and pathways involved in AD.
Highlights
Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis
We separated the 24 modules into four categories based on the median differential expression (DE) and differential co-expression (DC) scores: high DE and high DC (HDC_HDE), high DE and low DC (HDE_LDC), low DE and high DC (LDE_HDC), and low DE and low DC (LDE_LDC; Fig. 1a)
Because the modules with high differential expression were enriched with neuronal and microglia functions, pathways, and genes previously linked to AD pathology, we examined their associations with clinicopathological features
Summary
Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis. Previous studies of gene expression in bulk brain tissues identified microglia-associated genes and gene networks that were differentially expressed between AD and healthy control tissues[11,12,13,14,15] Those studies did not account for changes in cell-type composition between AD samples and healthy brain tissues, . It is not clear whether bona fide transcriptional regulation can be revealed on top of changes in cell-type composition in bulk tissue samples To answer those questions, we re-examined differences in gene expression between bulk brain tissues affected by AD and control samples in five large transcriptomic datasets (Table 1), while accounting for changes in the cell-type composition of the samples. If the DE is accompanied by DC, the DE is probably due to transcriptional regulation
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