STREM2 Mediates The Associations Of Minimal Depressive Symptoms With Amyloid Pathology In Prodromal Alzheimer’s Disease:The CABLE Study

Objective:Previous large longitudinal follow-up studies have observed an association between depression symptoms and an increased risk of Alzheimer’s disease(AD),but the relationship between the two is not yet fully understood.Studies suggest that neuroinflammation represented by activated microglia plays an important role in the pathogenesis of both depression and AD.Furthermore,cerebrospinal fluid(CSF)soluble triggering receptor expressed on myeloid cell 2(sTREM2),which is closely related to microglial activation,has been shown to change with AD pathology.However,the relationship between sTREM2 and minimal depressive symptoms(MDS),a clinical manifestation that presents with depressive symptoms but has not yet reached the diagnostic criteria for depression,and its relationship with both MDS and AD pathology remain unclear.The aim of this study is to explore the relationships between these three factors.Methods:796 cognitively normal participants were recruited from the Chinese Alzheimer’s Biomarker and Lifestyle(CABLE)study.The depressive symptoms were assessed using the Hamilton Depression Rating Scale(HDRS).Levels of CSF sTREM2,amyloid β(Aβ)42,phosphorylated tau(Ptau),and total tau(Tau)were measured using enzyme-linked immunosorbent assay(ELISA).Participants were divided into MDS(≥1 and ≤7)and Normal(=0)groups(NG)based on their HDRS scores.First,we used Data Analyses with Bootstrap-coupled ESTimation(DABEST)to evaluate differences in CSF sTREM2 levels between MDS and NG.Secondly,we used multiple linear regression analysis to examine the relationship between MDS and sTREM2,AD pathology(CSF Aβ42,CSF Ptau,and CSF Tau,as well as their ratios),and cognition,adjusting for age,gender,years of education,and Apolipoprotein E(APOE)ε4 carrier status.Finally,we used causal mediation analysis to explore whether sTREM2 can regulate the relationship between MDS and AD pathology.Additionally,we conducted the same statistical analysis in subgroups stratified by gender,age,and APOE ε4 carrier status.Results:In the whole population and the subgroups,MDS individuals exhibit lower levels of CSF sTREM2 compared to NG individuals.The results of multiple linear regression suggest that MDS is associated with lower sTREM2 levels(p<0.0001),lower CSF Aβ42(p<0.0001),and poorer cognitive performance(Mini-Mental State Examination,MMSE,p=0.0014),but not with tau-related pathology(CSF Ptau and CSF Tau).The results of the mediation model suggest that sTREM2 partially mediates the relationship between MDS and CSF AD pathology(p<0.0001),with mediation proportions ranging from 2.91%to 32.58%.Additionally,we found that sTREM2 and amyloid jointly mediate the impact of MDS on cognition.It is noteworthy that in subgroup analyses,the results of the aforementioned statistical models were most significant in the non-APOE ε4 carrier group.Conclusions:In summary,our research findings indicate a close correlation between early depressive symptoms and microglial activation,with no age or gender differences observed.Furthermore,we have also observed a strong association between early depressive symptoms and AD amyloid pathology.Additionally,microglial activation represents neuroinflammation that plays an important regulatory role in the association between early depressive symptoms and AD pathology.The relationship among these three factors is particularly significant in individuals who do not carry the APOE ε4 risk allele.This provides a potential treatment strategy for patients with early-stage AD who experience depressive symptoms,as targeting sTREM2 may reduce amyloid protein deposition and improve cognitive function.