Higher CSF sTREM2 attenuates APOE ε4‐related risk for amyloid pathology in cognitively intact adults: The CABLE study

The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein found in microglia within the brain, and its soluble form (sTREM2) has been shown to reduce amyloid deposition. Whether elevated TREM2-mediated microglial activity decreases the risk of Alzheimer's disease (AD) is unclear. The aim of this study was to assess whether high cerebrospinal fluid (CSF) levels of sTREM2 attenuate the risk of APOE ε4-associated amyloid pathology. We included 877 cognitively intact subjects from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, including APOE ε4 carriers (n = 136) and non-carriers (n = 741). The linear regression was used to examine the interaction effect between CSF sTREM2 levels and APOE ε4 status on CSF Aβ42 levels. Additionally, subgroup analyses stratified by sex and age were conducted. Our main finding was that higher concentrations of CSF sTREM2 attenuated the effect of APOE ε4 carriage (i.e., the sTREM2 × APOE ε4 interaction) on amyloid deposition (β = -2.701e-05, p = 0.023). Subgroup analyses showed that the effect of interaction was still significant only in male (p = 0.041) and mid-life (p = 0.013) subgroups. Our study suggested that in cognitively intact individuals, changes in sTREM2 levels are associated with biomarkers of AD, and higher concentrations of CSF sTREM2 attenuated the risk of APOE ε4-related amyloid pathology. The identified role of the sTREM2 × APOE ε4 interaction in amyloid pathology offers new insights into potential strategies for AD prevention in APOE ε4 carriers.