Differential transcript usage unravels transcriptional alterations in Alzheimer's disease human brains

Alzheimers disease (AD) is the leading cause of dementia in aging individuals. However pathophysiological processes involved in the brain are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain has been proposed to help for a better knowledge of the disease processes. In this work, we compared the differential expression of genes in different regions (temporal and frontal lobes) of the brain of healthy and AD adult subjects using data from three large studies: MAYO Clinic; Mount Sinai Brain Bank (MSBB) and ROSMAP. We show that gene expression is dramatically altered in the temporal lobe (TL), but not in the frontal lobe (FL), suggesting regional specificities in transcriptional alterations. Moreover, we show that a large set of genes undetected in the classical differential expression (DEG) analysis show alterations in the transcript usage ratio in AD, i.e. differential isoform fractions. Interestingly, the number of genes with differential transcript usage (gDTUs) is highest at advanced Braak stages and correlates with altered expression of genes associated with the splicing machinery. Using single-cell RNA sequencing (scRNAseq) data, we further assigned DEGs and gDTUs to individual cell types of the adult brain and observed similar signatures per cell type as to other two scRNAseq studies in AD. Lastly, we show that 52 out of 116 genes located in the loci associated with AD risk and expressed in the adult human brain present DEG and/or gDTUs in the TL, whereas only 13 are altered in the FL of AD patients. Among those altered genes, we detect an increased expression of APP isoforms containing the Kunitz protease inhibitor (KPI) domain, which is associated with plaque deposition. Altogether, our work proposes a novel integrative strategy to analyze transcriptional data in AD based on both gene/transcript expression and cell-type specificities.