FunGen-AD-supported research identifies modulators of the Alzheimer’s disease biomarker sTREM2

Previous research has shown that levels of the protein sTREM2 in cerebrospinal fluid (CSF) decrease in the early stages of Alzheimer’s disease (AD) compared with cognitively normal individuals; however, these sTREM2 levels are higher than normal in late-stage AD. The role of these fluctuations in AD progression is unknown. An international group of researchers, led by FunGen-AD researcher Carlos Cruchaga, conducted the largest GWAS study to date of sTREM2 in CSF to identify genetic modifiers. This analysis identified four loci associated with sTREM2 levels in CSF; two of these loci were found to be CSF-specific (i.e., not associated with plasma sTREM2). Functional genomics approaches were implemented to identify the gene driving the association in two of the loci, demonstrating that TGFBR2, in chr 3 and NECTIN2, in chr19 are implicated on TREM2 biology. The researchers also conducted Mendelian randomization and found that the genes involved in regulating sTREM2 levels—TREM2, MS4A, TGFBR2, and NECTIN2—are part of the causal pathway for AD, suggesting that modulation of sTREM2 levels are potential therapeutic targets for Alzheimer’s disease.

This research was partially supported by FunGen-AD grant RF1AG058501 and is published in Molecular Neurodegeneration here. You can read more about the research findings at the following link:

  • Alzheimer’s biomarker sTREM2 plays a causal, potentially modifiable, role in disease (Medical Xpress)