Key Points
Early-stage alterations were evident in peripheral sTREM2-related inflammatory activity.
These alterations implicate early inflammatory cell development and recruitment signaling in AD.
Patterns of inflammatory activity are altered across all AD stages.
Abstract
Alzheimer’s disease (AD) has been linked to multiple immune system–related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage–dependent manner. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between peripheral sTREM2 and an altered peripheral immune response in AD. The objective of this study was to explore the relationship between human plasma sTREM2 and inflammatory activity in AD. The hypothesis of this exploratory study was that sTREM2-related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across AD stages that implicate early-stage alterations in peripheral sTREM2-related inflammatory activity in AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost in later AD-related stages with high levels in mild cognitive impairment. Although multiple other inflammatory factors either differed significantly between groups or were significantly correlated with sTREM2 within specific groups, three inflammatory factors (fibroblast growth factor-2, GM-CSF, and IL-1β) are notable because they exhibited both lower levels in AD, compared with mild cognitive impairment, and a change in the relationship with sTREM2. This evidence provides important support to the hypothesis that sTREM2-related inflammatory activity alterations are AD stage specific and provides critical information for therapeutic strategies focused on the immune response.
Footnotes
This work was supported by U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Aging R01AG066707 (F.C.), 3R01AG066707-01S1 (F.C.) R56AG063870 (L.M.B.), P30 AG062428 (J.B.L.), R01AG022304 (S.R.), Cleveland Clinic Foundation Center of Excellence Award (J.B.L. and T.B.), the Jane and Lee Seidman Fund (J.B.L.), and the Aging Mind Foundation (L.M.B.).
G.E.W. analyzed and interpreted data, prepared figures, and wrote the manuscript text. M.K. performed assays and prepared data. E.D.T. analyzed data and prepared figures. Y.S. developed assays. J.P. and S.R. characterized participants’ clinical status and performed neurological testing. H.F., Y.Z., and F.C. contributed analyses, figure development, and manuscript editing. T.M.D. and S.S. contributed results interpretation and manuscript development. J.B.L. performed neurological testing, participant consensus, data interpretation, and manuscript development. L.M.B. oversaw the study design, assays completion, analysis, figure development, and manuscript preparation. All authors read and approved the final manuscript.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- Aβ
- amyloid β
- AD
- Alzheimer’s disease
- APOE
- apolipoprotein E
- ATN
- amyloid β, phosphorylated tau, and neurodegeneration
- CADRC
- Cleveland Alzheimer’s Disease Research Center
- CN
- cognitively normal
- EGF
- epidermal growth factor
- FGF
- fibroblast growth factor
- GRO
- growth-regulated oncogene
- IL-1RA
- IL-1 receptor agonist
- IP-10
- IFN-γ–inducible protein 10 kDa
- LRCBH-Biobank
- Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank
- MCI
- mild cognitive impairment
- MCP
- monocyte chemotactic protein
- MDC
- macrophage-derived chemokine
- MFI
- mean fluorescence intensity
- MIP
- macrophage inflammatory protein
- p-Tau181
- phosphorylated- tau181
- sCD40L
- soluble CD40 ligand
- sTREM2
- soluble triggering receptor expressed on myeloid cells 2
- t-Tau
- total tau
- TREM2
- triggering receptor expressed on myeloid cells 2
- VEGF
- vascular endothelial growth factor
- Received August 5, 2021.
- Accepted March 7, 2022.
- Copyright © 2022 by The American Association of Immunologists, Inc.
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