Differential gene expression in genetic and early‐onset Alzheimer's disease in two biological samples: Brain tissue and lymphoblastoid cell lines: Genetics/omics and systems biology.

Background: Several previous studies have analyzed the genetic expression in late‐onset Alzheimer's disease (AD). In this study, we aim to analyze the differential gene expression between sporadic early‐onset AD (sEOAD) and autosomal dominant AD due to the presence of PSEN1 mutations (PSEN1) in two type of samples, brain tissue and lymphoblastoid cell lines (LCL). Method: Frozen prefrontal cortex (5 CTRL, 4 sEOAD and 4 PSEN1) was obtained from the Neurological Tissue Bank and LCL (5 CTRL, 5 sEOAD and 5 PSEN1) from the Alzheimer's Disease Unit, both from the Hospital Clinic of Barcelona, IDIBAPS. Gene expression was measured with microarray Clariom D (Affymetrix). Differentially expressed genes (DEG) were obtained selecting the 35% most variable genes (n = 8473) by adjusting a linear model with empirical Bayes moderation of the variance. Significance threshold was set at p.value < 0.05 and fold change in absolute value >0.5. The analysis of biological significance was based on gene set enrichment analysis on Reactome Pathway Knowledge database. Result: 781/355 (brain/LCL) genes were differentially expressed in the sEOAD vs CTRL comparison, 503/275 in the PSEN1 vs CTRL, and 244/115 in the PSEN1 vs EOAD. No DEG were found with a significance threshold of an adjusted p.value <0.05. Any of the DEG survived after multiple comparisons correction. The top 10 enriched pathways for each comparison, using the most significative p.value and a normalized enrichment score (NES) absolute value >1.8, were considered. Pathways involved in synapsis were found in 2 comparisons: sEOAD vs CTRL (brain) and PSEN1 vs CTRL (LCL). Pathways related to metabolism (mainly Krebs cycle) were identified in all comparisons between patients and controls in both tissues. Signal transduction pathways were found in all comparisons. Immune system was observed in all comparisons between PSEN1 and sEOAD, as well as sEOAD vs CTRL in brain. Conclusion: Genes involved in the immune system and signal transduction pathways were differentially expressed in sporadic and autosomal dominant AD caused by PSEN1 mutations. The number of DEG was higher in brain tissue than in LCL comparisons. Validation of these findings by quantitative‐PCR would be necessary to discard false positive results. [ABSTRACT FROM AUTHOR]