Sex‐ or depression‐specific relationships with CSF sAPPα, sAPPβ and their associations with CSF sTREM2 in older adults

Abstract

AbstractBackgroundFemale sex and depression are associated with increased risk for Alzheimer’s disease (AD) but the mechanisms for the increased risk remain poorly understood. Increased brain amyloid deposition and microglial activation have both been implicated; however, the role of sex‐ and depression‐related effects on microglial activation remain understudied.Both sAPPα and sAPPβ, cleavage products of non‐amyloidogenic and amyloidogenic APP cleavage, respectively, have been reported to induce microglial activation. These observations prompted us to examine the relationships between sex, depression, and levels of sAPPα and sAPPβ. CSF levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is a possible proxy for phagocytic anti‐inflammatory TREM2‐dependent microglial activation, was also examined.MethodFifty‐one cognitively intact subjects (31 subjects with late‐life major depression (LLMD) and 20 controls) aged 60 years and older, completed a 3‐year longitudinal study. Independent‐samples Mann‐Whitney‐U tests were used to examine group differences by diagnosis, sex, and APOE genotype for sAPPα and sAPPβ.ResultThere were no significant differences between subjects with LLMD and Controls in CSF sAPPα or sAPPβ levels. Irrespective of diagnosis, females had significantly higher levels of both sAPPα (p = 0.016) and sAPPβ (p = 0.010) compared to males. sAPPα and sAPPβ were significantly correlated with each other (rho = 0.930, p<0.001). In the whole sample, sTREM2 correlated with both sAPPα (rho = 0.462, p = 0.001) and sAPPβ (rho = 0.504, p<0.001). When examining the relationships as a function of diagnosis, sAPPα was found to be associated with sTREM2 in Controls only (rho = 0.474, p = 0.035) while sAPPβ correlated with sTREM2 in LLMD only (rho = 0.370, p = 0.048). When examining the relationship as a function of sex, we found that sTREM2 significantly correlated with both sAPPα (rho = 0.629, p = 0.002) and sAPPβ (rho = 0.673, p = 0.001) in females but not in males (sAPPα: rho = 0.310, p = 0.109; sAPPβ: rho = 0.341, p = 0.076).ConclusionMean CSF sAPPα and sAPPβ levels between Controls and LLMD showed no group differences but were significantly increased in females compared to males. Females but not males showed significant positive associations between CSF sTREM2, sAPPα and sAPPβ. Future studies should determine if these results are associated with differences in microglial activation and to the increased risk for AD and depression in females.