Fluid and imaging amyloid‐beta biomarkers discordant individuals present different blood transcriptomic phenotypes
Thomas Hugentobler Schlickmann, Marco Antônio de Bastiani, Bruna Bellaver, Hussein Zalzale, Lara Angi Souza, Luiza Santos Machado, Andreia Silva da Rocha, Lucas Uglione Da Ros, João Pedro Ferrari‐Souza, Giovanna Carello‐Collar, Gabriela Lazzarotto, Christian Limberger, Lavínia Perquim de Carvalho, Pedro Vidor, Wyllians Vendramini Borelli, Francieli Rohden, Tharick A. Pascoal, Eduardo R. Zimmer,- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Cerebrospinal fluid (CSF) and Positron emission tomography (PET) amyloid‐β biomarkers are commonly used interchangeably to measure amyloid‐β deposition, an early event in the development of Alzheimer’s disease (AD). However, it is not uncommon to find individuals with discordant measurements of amyloid‐β CSF and PET. It has been hypothesized that this discordance may be an intermediate step between the CSF and brain amyloid deposition, and that discordant individuals might be in different disease stages or have different disease phenotypes. Here, we applied blood transcriptomic analysis to evaluate differences in amyloid‐β CSF and PET discordant and concordant individuals.
Method
We analyzed the blood transcriptome of 200 individuals from the ADNI cohort who had measurements of both CSF amyloid‐β42 and [18F]Florbetapir PET at baseline and at 2‐year follow‐up. The demographic characteristics of the sample are presented in table 1. Our analysis yielded four groups: CSF+/PET‐ (n = 18), CSF‐/PET+ (n = 19), CSF+/PET+ (n = 76), and CSF‐/PET‐ (n = 87). The latter was the control group for all analyses. Differentially expressed genes (DEGs, uncorrected p‐value < 0.01) were used for gene set enrichment analysis (GSEA) to identify group‐specific altered biological pathways.
Result
CSF+/PET‐, CSF‐/PET+ and CSF+/PET+ individuals showed a great proportion of unshared DEGs (Figure 1). The CSF+/PET‐ group, which is thought to represent a very early stage in the disease, presented the highest number of unshared DEGs (273) with upregulated GO terms involved mainly in metabolic processes. The CSF‐/PET+ group possessed 113 unique DEGs, while the CSF+/PET+ possessed 47. Interestingly, these groups presented similar alterations in biological processes, representing mainly alterations in immune response and inflammation.
Conclusion
Our results highlight the differences in the blood transcriptomic phenotype between CSF and PET amyloid‐β concordant and discordant individuals. Importantly, individuals very early in the AD continuum (CSF+/PET‐) presented the most distinct phenotype. Our results suggest that blood transcriptomics are able to capture subtle changes in brain amyloid‐β and might help identify individuals in different stages of AD.