Research ArticleAlzheimer’s Disease

The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk

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Science Translational Medicine  14 Aug 2019:
Vol. 11, Issue 505, eaau2291
DOI: 10.1126/scitranslmed.aau2291

TREM2 takes center stage

Genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with Alzheimer’s disease (AD) risk. Soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) change with AD progression; however, genetic modifiers of CSF sTREM2 remain unknown. Deming and colleagues now report two independent genetic associations in the membrane-spanning 4-domains subfamily A (MS4A) gene region. An AD risk variant was associated with reduced CSF sTREM2 concentrations, whereas a different variant leading to reduced AD risk was associated with elevated CSF sTREM2 concentrations. Gene expression analyses and molecular studies of human macrophages validated a functional relationship between MS4A4A and sTREM2 concentrations.

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