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. 2019 Jul;6(7):1248-1262.
doi: 10.1002/acn3.50827. Epub 2019 Jul 4.

Key inflammatory pathway activations in the MCI stage of Alzheimer's disease

Jagan A Pillai  1   2   3 , Sean Maxwell  4   5 , James Bena  6 , Lynn M Bekris  7 , Stephen M Rao  1   2 , Mark Chance  4   5 , Bruce T Lamb  8 , James B Leverenz  1   2   3 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Key inflammatory pathway activations in the MCI stage of Alzheimer's disease

Jagan A Pillai et al. Ann Clin Transl Neurol. 2019 Jul.

Abstract

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.

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Conflict of interest statement

Full Financial Disclosures of all Authors for the Past Year:

Jagan A Pillai has obtained funding for research from the National Institutes of Health, Alzheimer’s Association and Keep Memory Alive foundation. Bruce T Lamb has received honoraria or consulting fees from Eli Lilly, Amgen and Eisai and research funding from the National Institutes of Health, US Department of Defense, the Alzheimer’s Association and the BrightFocus Foundation. Stephen M. Rao has received honoraria, royalties or consulting fees from: Biogen, Genzyme, Novartis, American Psychological Association, International Neuropsychological Society and research funding from the National Institutes of Health, US Department of Defense, National Multiple Sclerosis Society, CHDI Foundation, Biogen, and Novartis. James B. Leverenz has received consulting fees from Axovant, GE Healthcare, Navidea Biopharmaceuticals, Takeda, and Grant support from Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Biogen, Genzyme/Sanofi, Lundbeck, Michael J Fox Foundation, National Institute of Health. Sean Maxwell, James Bena, Lynn Bekris, Mark Chance declared no conflict of interest.

Figures

Figure 1
Figure 1
Methodological overview.
Figure 2
Figure 2
Cluster plot noting similar correlation ordering among the inflammatory analytes in ADNI and discovery cohorts, with shared ordering of analytes more notable in CSF than plasma measures.(Colored points: Pearson correlation coefficients of discovery and ADNI analytes, Connector lines: difference in correlation values for each analyte compared between the two datasets).
Figure 3
Figure 3
Network analysis dendrogram showing modules based on the coexpression topological overlap of genes related to inflammatory analytes and brain transcriptome. Color bars give information on module membership in they hold one or more analytes of significance identified in CSF and plasma. The table provides the related enrichment for KEGG pathways within these specific inflammation‐related gene clusters of interest and false discovery rate.
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