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Key inflammatory pathway activations in the MCI stage of Alzheimer's disease
Jagan A Pillai1,2,3, Sean Maxwell4,5, James Bena6
1Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio, 44195.
Objective:
To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD).
Methods:
A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aβ42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations. The pathways were additionally validated by evaluating genes related to all analytes in coexpression networks of brain tissue transcriptome from an autopsy confirmed AD cohort to interrogate if the same pathway activations were conserved in the brain tissue gene modules.
Results:
Analytes of the tumor necrosis factor (TNF) signaling pathway (KEGG ID:4668) in the CSF and plasma best correlated with CSF t-tau and p-tau levels, and analytes of the complement and coagulation pathway (KEGG ID:4610) best correlated with CSF Aβ42 levels. The top inflammatory signaling pathways of significance were conserved in the peripheral and the CNS compartments. They were also confirmed to be enriched in AD brain transcriptome gene clusters.
Interpretation:
A cell-protective rather than a proinflammatory analyte profile predominates in the CSF in relation to neurodegeneration markers among MCI-AD patients. Analytes from the TNF signaling and the complement and coagulation pathways are relevant in evaluating disease severity at the MCI stage of AD.
Insights
Key inflammatory pathways, including tumor necrosis factor (TNF) signaling and complement/coagulation, are activated in mild cognitive impairment (MCI) Alzheimer's disease (AD). These pathways correlate with AD biomarkers and are conserved across brain and blood, offering insights into disease progression.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline.
- Mild cognitive impairment (MCI) is an intermediate stage between normal aging and AD dementia.
- Identifying early inflammatory changes in MCI is crucial for understanding AD pathogenesis and developing interventions.
Purpose of the Study:
- To pinpoint the specific inflammatory pathways activated in both the central nervous system (CNS) and peripheral compartments during the MCI stage of AD.
- To correlate these inflammatory pathways with established AD biomarkers.
- To validate the conservation of these pathways in brain tissue.
Main Methods:
- A cross-sectional study design was employed, involving patients with MCI due to AD.
- Inflammatory analytes were measured in cerebrospinal fluid (CSF) and plasma using a multiplex platform.
- Correlations were drawn between analyte levels and AD biomarkers (CSF Aβ42, t-tau, p-tau).
- Pathway validation was performed using gene coexpression networks from AD brain tissue.
Main Results:
- Tumor necrosis factor (TNF) signaling pathway analytes in CSF and plasma correlated with CSF total tau (t-tau) and phosphorylated tau (p-tau).
- Complement and coagulation pathway analytes correlated with CSF amyloid-beta 42 (Aβ42) levels.
- Identified inflammatory pathways were conserved in both peripheral and CNS compartments and enriched in AD brain tissue gene modules.
Conclusions:
- A predominantly cell-protective, rather than pro-inflammatory, analyte profile was observed in the CSF relative to neurodegeneration markers in MCI-AD patients.
- TNF signaling and complement/coagulation pathways are significant in assessing disease severity at the MCI stage of AD.
- These findings highlight the role of specific inflammatory pathways in early AD pathogenesis and progression.