Levels of Immune Marker TREM2 Rise Years Before Alzheimer’s Disease Becomes Apparent

Researchers reported that TREM2 levels rise early on in the progression of Alzheimer’s disease, and that the biomarker might be useful in clinical research to evaluate the benefits of new AD therapies on neuroinflammation, or may one day be a therapeutic target itself.

Levels of an immune cell receptor called TREM2 were found to increase early on in the progression of Alzheimer’s disease (AD), before the onset of dementia but after amyloidosis and neuronal injury have occurred, researchers reported in the December 14, 2016 issue of Science Translational Medicine.

The finding that TREM2 is elevated fairly early in AD lends support to the belief that inflammation is part of the neuropathology of the disease, though amyloid deposition still seems to be the driving force behind it. TREM2 is expressed by microglia, and is seen as a biomarker for microglial activity.

“This finding supports the amyloid cascade hypothesis and adds the first innate immunity marker to a temporal model of AD progression,” the researchers wrote.

The study, conducted by AD researchers in Munich, Germany and Washington University in St. Louis, builds on previous research, including a key 2012 study that found that mutations in the TREM2 gene put people at elevated risk for AD. While the precise mechanisms at work with TREM2 and microglial activation in AD are not fully understood, researchers said the biomarker might be useful in clinical research to evaluate the benefits of new AD therapies on neuroinflammation, or may one day be a therapeutic target itself.

“We found that cerebrospinal fluid [CSF] soluble TREM2 [sTREM2] levels were abnormally increased about seven years before the onset of dementia symptoms but after changes in CSF amyloid-beta peptide and tau,” senior study author Christian Haass, PhD, professor at the German Center of Neurodegenerative Diseases in Munich, told Neurology Today in an email. “These results suggest that amyloid disposition occurs first and the neuroimmune response occurs only subsequently within the pathological cascade of events.”

Another study author, Michael Ewers, PhD, professor at the Institute for Stroke and Dementia Research in Munich, noted in an email that the rise in TREM2 levels, as measured in CSF, may be indicative of a “protective response to neuronal injury,” although potentially damaging neuroinflammation may follow microglial activation.

“Thus it remains to be confirmed whether increased TREM2 levels are reflective of a beneficial response of the immune system of the brain,” Dr. Ewers cautioned.

The findings raise the “important question of what the effects of modifying TREM2 activity may have for the course of disease progression,” Dr. Haass added.

The study authors noted in the report that 25 years after the amyloid hypothesis was proposed, multiple sources of evidence support the notion that the pathogenic sequence of AD is triggered by amyloid pathology, followed by neurofibrillary tangle degeneration and cognitive decline.

“However,” they wrote, “inflammatory events and, specifically, activation of microglia have been observed in basically all neurodegenerative disorders including AD, suggesting that the immune response plays an important part in the pathological cascade of neurodegeneration.”

STUDY DESIGN

The new study analyzed levels of sTREM2 in CSF of people with a genetic predisposition to AD. The samples were collected as part of the Dominantly Inherited Alzheimer Network (DIAN), a multicenter observational study that follows individuals with autosomal dominant AD (ADAD).

“The unique design of the DIAN project enabled us to investigate AD in its preclinical stages and to determine the trajectories of markers during the natural course of the disease,” the researchers explained in the journal article.

They analyzed data from 218 participants in the DIAN cohort, including 127 people with ADAD mutations and 91 non-carrier siblings, and found a higher increase in TREM2 in the pre-symptomatic phase in the ADAD group.

First author Marc Suarez-Calvet, MD, said “the increase in soluble TREM2 levels was highly correlated with an increase in CSF tau, suggesting that sTREM2 is closely related to neuroinjury.” He said the notion that TREM2 has a protective action is also supported by other recent research by the team that found that “TREM2 promotes antibody-mediated clearance of amyloid plaques.”

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