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Research Findings Suggest TREM2 Levels Could Serve as Biomarker During Alzheimer's Progression

NEW YORK (360Dx) – A protein shed into the cerebrospinal fluid acts as a marker of inflammation during early Alzheimer's disease development, researchers from Germany and the US have found.

Alzheimer's disease is thought to be driven by the accumulation of amyloid-beta, which then leads to a cascade of events, including the development of plaques, to bring on cognitive decline. At the same time, inflammatory events and the activation of microglia are suspected to have a role in disease development, though how they fit into that progression has been unclear.

Since mutations in the TREM2 gene, which encodes an innate immune receptor protein found on microglia and other cell surfaces, have been linked to an increased risk of developing Alzheimer's disease, the researchers sought to examine the levels of its soluble variant, sTREM2, in people with autosomal dominant Alzheimer's disease and their unaffected siblings. They also sought to better understand the role of inflammation in disease progression.

As they reported today in Science Translational Medicine, the investigators found that levels of sTREM2 in the cerebrospinal fluid were increased in the affected siblings, even some five years before the expected onset of symptoms.

"TREM2 levels could therefore be a biomarker used to track immune activity while Alzheimer's is progressing," co-senior author Michael Ewers from the Ludwig-Maximilians-Universität in Munich said in a statement.

Ewers and his colleagues used an ELISA assay they developed to evaluate cerebrospinal fluid sTREM2 levels in 218 people from the Dominantly Inherited Alzheimer Network (DIAN) cohort. One hundred and twenty-seven of these participants carried mutations in PSEN1, PSEN2, or APP, while the remaining 91 were unaffected siblings of the carriers.

After adjusting for age, gender, and APOE ε4 status, the affected siblings had increased sTREM2 as compared to the unaffected siblings.

Using a linear mixed model approach, the researchers examined changes in sTREM2 levels during disease progression. They found that differences in sTREM2 between affected and unaffected siblings started to become apparent about five years before the expected onset of symptoms. They gauged that timing of symptom onset based on when the patient's parent began exhibiting symptoms.

This difference in sTREM2 levels remained significant, the researchers noted, until about five years after symptoms arose. After that, the differences were no longer statistically significant, possible due to the lower number of patients with later-stage disease.

Ewers and his colleagues similarly reported that sTREM2 levels varied significantly between affected siblings with very mild and mild dementia and their unaffected siblings. However, affected siblings with severe dementia did not have significantly increased sTREM2 levels, though the researchers again noted that they had low numbers of patients at this later disease stage.

When the researchers compared this time course of sTREM2 level changes to other biological markers of disease, they found that this increase in sTREM2 levels occurs after Aβ deposition and after an increase of tau in cerebrospinal fluid.

Based on this, the researchers narrowed in on the timing of microglial activation, as gauged by sTREM2 levels, placing it as occurring between amyloidosis and neuronal injury — which themselves often occur some 15 years before symptoms start — and the onset of symptoms. This, they added, is in line with the amyloid cascade hypothesis that says that amyloid drives disease progression. The investigators suggested that the increase in sTREM2 could reflect a response to an early and subtle neuronal injury.

While sTREM2 levels in the cerebrospinal fluid can't be used as a diagnostic marker because they overlap between patients and controls, they could be used to track microglial activity during disease progression, the researchers noted. It also could be used, they added, to monitor the efficacy of drugs targeting inflammation.

"In this regard, it will be interesting to follow changes in sTREM2 during anti-Aβ immunotherapeutic studies," Ewers and his colleagues wrote in their paper.