Blood transcriptomics differentiate tau positive discordant and concordant individuals
Lara Angi Souza, Thomas Schlickmann, Luiza Santos Machado, Tharick A. Pascoal, Marco Antônio De Bastiani, Eduardo R Zimmer- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Levels of soluble hyperphosphorylated tau (p‐tau) in the cerebrospinal fluid (CSF) and tau tangles measured by positron emission tomography (PET) are used to determine tau positivity in Alzheimer’s disease (AD). However, a mismatch between CSF and PET positivity occurs in some cases. In fact, it is thought that CSF tau biomarker abnormalities may precede changes in tau‐PET imaging. With this in mind, the aim of our study was to examine the blood transcriptomic phenotypes in individuals presenting tau positivity biomarker discordance.
Method
Blood transcriptomics data from 64 individuals (cognitively unimpaired = 31 and cognitively impaired = 33) were obtained from the ADNI database. We divided these individuals into negative (CSF‐PET‐), discordant (CSF‐PET+ and CSF+PET‐) and positive group (CSF+PET+) to tau biomarkers. We also performed differential expression analyses (DEA) using the limma package. Additionally, we conducted a KEGG pathway enrichment analysis using altered genes obtained from DEA (p‐value < 0.05). Amyloid B42, total tau, Mini Mental State Examination, Clinical Dementia Rating Sum of Boxes, APOE4 status, education, and gender difference in the groups were described in Fig1. Data were analyzed with Pearson’s Chi‐squared test and Linear Model ANOVA. All statistical analyses were performed in R.
Result
Our analysis revealed that discordant and positive individuals had, respectively, 1191 and 314 DEGs if compared to negative individuals. Interestingly, we found 324 DEGs in common between them (Fig2A‐C). In the KEGG functional enrichment analysis (Fig3), we observed that the main terms were enriched in the tau discordant individuals were related to aminoacids metabolism and inflammation (Fig3A). In the CSF+/PET+ individuals pathways related to calcium signaling and viral response were the most altered compared to CSF‐/PET‐ (Fig3B).
Conclusion
Our results indicate that blood transcriptome differs among tau negative, discordant and positive individuals. This suggests that multiple biological pathways in the blood are dependent on tau changes. Further investigation of DEGs clusters possibly could demonstrate new insights about tau mechanisms involved in the disease.