Research News

A new study led by Lynn Bekris, PhD, Associate Staff in the Genomic Medicine Institute, suggests that inflammatory activity related to the sTREM2 protein may be linked to Alzheimer’s disease (AD) progression. Published in the Journal of Immunology, the findings provide evidence that targeting inflammation in the early stages of Alzheimer’s disease may be a feasible treatment strategy.

Genetic studies have demonstrated that variants of the gene that produces TREM2, a protein associated with inflammatory factor activity, significantly increase the risk for AD. Notably, levels of the protein’s soluble form, sTREM2, have been found to be elevated in cerebrospinal fluid (CSF, the liquid found in the central nervous system) during the early stages of AD.

“In this study, we investigated the connection between sTREM2 and inflammatory activity in relation to the different stages of the AD continuum,” said Dr. Bekris. “We specifically examined levels of sTREM2 and inflammatory factors in blood plasma, instead of CSF, since less is known about the role of the peripheral immune response, or the immune activity occurring outside of the central nervous system, in AD.”

sTREM2-related inflammatory activity altered in early AD

The researchers utilized a cohort of 200 individuals classified into three disease stages of AD: cognitively normal (88), mild cognitive impairment (37) and AD dementia (75). They further categorized a subset of the cohort based on the ATN continuum, a research framework that classifies AD patients based on CSF biomarkers of amyloid plaques, tau neurofibrillary tangles (two hallmarks of AD-related brain changes) and neurodegeneration.

Analyzing the levels of plasma sTREM2 and multiple inflammatory factors, including anti- and pro-inflammatory cytokines, across the different stages of AD (defined by positivity for CSF amyloid or tau biomarkers or by clinical assessment), the researchers found different patterns of sTREM2-related inflammatory activity that were specific to AD stage. Notably, they identified connections between sTREM2 and inflammatory factors that were much stronger in the groups without AD symptoms or CSF biomarkers, compared to the groups with symptoms or CSF biomarkers.

The researchers also identified several inflammatory factors that had significant relationships with sTREM2 and AD stage. Notable inflammatory factors that had both a significant relationship with sTREM2 and significantly different levels across groups were GM-CSF, FGF-2, IL-1β and fractalkine. 

“Overall, we observed severe dampening or uncoupling of the relationship between sTREM2 and various inflammatory factors in the early stages of AD that became less severe in the later stages,” said Dr. Bekris. “Our study was a small, exploratory investigation, so additional studies are needed to help tease apart these inflammatory effects on AD disease progression, but undoubtedly our findings provide further evidence that early elevation of sTREM2 plays a critical role in AD and that sTREM2-related inflammatory activity may serve as a stage-specific biomarker of AD progression.”

Grace Weber, PhD, a former postdoctoral fellow in the Bekris lab, was first author on the study, which was supported by the National Institute on Aging (part of the National Institutes of Health), Cleveland Clinic Center of Excellence Award Program, the Aging Mind Foundation and the Jane and Lee Seidman Fund.