Peripheral sTREM2-related inflammatory activity alterations in early stage Alzheimer’s disease

Alzheimer’s disease (AD) has been linked to multiple immune system genetic variants, implicating potential broad alterations in inflammatory profiles in the disease. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. A soluble TREM2 isoform (sTREM2) is elevated in cerebrospinal fluid in the early stages of AD suggesting it may be a biomarker of progressive alterations in immune response to AD-related pathology. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between plasma sTREM2 and the altered peripheral immune response in AD. The objective of this exploratory study was to examine the relationship between sTREM2 and inflammatory activity in human participants defined by clinically characterized cognitive symptoms and groups defined by the cerebrospinal fluid biomarkers amyloid beta, phosphorylated tau, and neurodegeneration (NIA-AA Research Framework: “ATN continuum”.) The hypothesis of this exploratory study was that sTREM2 related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across disease groups and ATN categories that implicates peripheral sTREM2 related inflammatory activity as altered in the early stages of AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost as disease progressed, and fractalkine, IL-5 and IL-17A were decreased in AD. These preliminary data provide important support to the hypothesis that sTREM2-related inflammatory activity is a stage-specific biomarker of AD progression, providing the groundwork for future studies and therapeutic strategies. ### Competing Interest Statement The authors have declared no competing interest. * List of abbreviations : AD : Alzheimer’s disease TREM2 : triggering receptor expressed on myeloid cells 2 sTREM2 : soluble triggering receptor expressed on myeloid cells 2 ATN : amyloid beta, phosphorylated tau, and neurodegeneration Aβ : amyloid beta CSF : cerebrospinal fluid CN : cognitively normal MCI : mild cognitive impairment p-Tau : phosphorylated tau t-Tau : total tau LRCBH-Biobank : Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank CADRC : Cleveland Alzheimer’s Disease Research Center CBC : Complete blood counts APOE : apolipoprotein E EGF : Epidermal Growth Factor FGF-2 : Fibroblast Growth Factor 2 TGF-α : Transforming Growth Factor alpha G-CSF : Granulocyte-colony stimulating factor Flt-3L : FMS-like tyrosine kinase 3 ligand GM-CSF : Granulocyte-Macrophage Colony Stimulating Factor IFN : interferon GRO : growth-regulated oncogene IL : interleukin MCP : Monocyte chemotactic protein MDC : Macrophage-derived chemokine sCD40L : soluble CD40-ligand IL-1RA : interleukin 1 receptor agonist IP-10 : interferon-gamma inducible protein MIP : macrophage inflammatory protein TNF : tumor necrosis factor VEGF : Vascular Endothelial Growth Factor MFI : Mean fluorescence intensity