BACKGROUND

Alzheimer's disease (AD) is associated with abnormal tau and amyloid-β accumulation in the brain, leading to neurofibrillary tangles, neuropil threads and extracellular amyloid-β plaques. Treatment is limited to symptom management, a disease-modifying therapy is not available. To advance search of therapy approaches, there is a continued need to identify targets for disease intervention both by confirming existing hypotheses and generating new hypotheses.

METHODS

We conducted a mRNA-seq study to identify genes associated with AD in post-mortem brain samples from the superior temporal gyrus (STG, n ​= ​76), and inferior frontal gyrus (IFG, n ​= ​65) brain regions. Differentially expressed genes (DEGs) were identified correcting for gender and surrogate variables to capture hidden variation not accounted for by pre-planned covariates. The results from this study were compared with the transcriptome studies from the Accelerated Medicine Partnership - Alzheimer's Disease (AMP-AD) initiative. Over-representation and gene set enrichment analysis (GSEA) was used to identify disease-associated pathways. Protein-protein interaction (PPI) and weighted gene co-expression network analysis (WGCNA) analyses were carried out and co-expressed gene modules and their hub genes were identified and associated with additional phenotypic traits of interest.

RESULTS

Several hundred mRNAs were differentially expressed between AD cases and cognitively normal controls in the STG, while no and few transcripts met the same criteria (adjusted p less than 0.05 and fold change greater than 1.2) in the IFG. The findings were consistent at the gene set level with two out of three cohorts from AMP-AD. PPI analysis suggested that the DEGs were enriched in protein-protein interactions than expected by random chance. Over-representation and GSEA analysis suggested genes playing roles in neuroinflammation, amyloid-β, autophagy and trafficking being important for the AD disease process. At the gene level, 10 genes from the STG that were consistently differentially expressed in this study and in the MSBB study (one of the three cohorts within the AMP-AD initiative) were enriched in microglial genes (TREM2, C3AR1, ITGAX, OLR1, CD74, and HLA-DRA), but also included genes with a broader cell type expression pattern such as CDK2AP1. Among the DEGs with supporting evidence from an independent study, CDK2AP1 (most abundantly expressed in astrocyte) was the transcript with strongest association with antemortem cognitive measure (last Mini-Mental State Examination score) and neurofibril tangle burden but also associated with amyloid plaque burden, while OLR1 was the transcript with strongest association with amyloid plaque burden. GSEA and over-representation analyses revealed gene sets related to immune processes including neutrophil degranulation, interleukin 10 signaling, and interferon gamma signaling, complement and coagulation cascades, phosphatidylinositol signaling system, phagosome and neurotransmitter receptors and postsynaptic signal transmission were enriched from this study and replicated in an independent study.

CONCLUSION

This study identified differential gene sets, common with two out of three AMP-AD cohorts (ROSMAP and MSBB) and highlights microglia and astrocyte as the key cell-types with DGEs associated with AD clinical diagnosis, and/or antemortem cognitive measure as well as neuropathological indices. Future meta-analysis and causal inferential analysis will be helpful in pinpointing the most relevant pathways and genes to intervene.