Research ArticleAlzheimer’s Disease

Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury

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Science Translational Medicine  14 Dec 2016:
Vol. 8, Issue 369, pp. 369ra178
DOI: 10.1126/scitranslmed.aag1767

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Microglial activation in AD

Little is known about the role of microglia in Alzheimer’s disease (AD). TREM2 is a protein expressed by microglia. Mutations in TREM2 increase the risk for neurodegenerative diseases including AD. Suárez-Calvet and colleagues have measured the amount of a secreted form of TREM2 (sTREM2) as a surrogate marker for microglial activation. They measured sTREM2 in the cerebrospinal fluid (CSF) of a unique cohort of 127 subjects with autosomal dominant AD and 91 healthy siblings. CSF sTREM2 was abnormally increased 5 years before the expected onset of symptoms in the AD patients. This increase occurred after alterations in markers for brain amyloidosis and neuronal injury.

Abstract

Emerging evidence supports a role for innate immunity and microglia in Alzheimer’s disease (AD) pathophysiology. However, no marker related to microglia has been included in the temporal evolution models of AD. TREM2 is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders. Its ectodomain is released by proteolysis as a soluble variant (sTREM2) and can be detected in the cerebrospinal fluid (CSF). In patients with autosomal dominant AD, we tested how many years before the expected symptom onset did CSF sTREM2 increase in mutation carriers (MCs) compared to noncarriers (NCs). We also determined the temporal sequence of changes in CSF sTREM2 and markers for amyloid deposition and neurodegeneration as well as cognitive performance. We included 218 participants consisting of 127 MC and 91 NC siblings from the Dominantly Inherited Alzheimer Network. We observed that CSF sTREM2 increased in MCs compared to NCs 5 years before the expected symptom onset and this difference remained significant until 5 years after the expected symptom onset. Changes in CSF sTREM2 occurred after alterations were observed in markers for brain amyloidosis and neuronal injury. We propose that microglial activation occurs several years before the expected symptom onset, but after amyloidosis and neuronal injury have already occurred.

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