STREM2 And GFAP Mediated The Association Of Insulin-like Growth Factor Binding Protein 2 With AD Pathology

Objective:Recent studies have shown that insulin resistance plays a crucial role in the pathogenesis of Alzheimer’s disease（AD）.However,the mechanism of insulin resistance affecting AD remains unclear.Recently,insulin resistance has been observed in animal models to participate in the biological process of AD pathology through activation of microglia and astrocytes.The abnormal insulin-like growth factor 1（IGF-1）signaling,as an important part of insulin resistance,has been considered to be a key factor in the pathogenesis of AD.Therefore,we speculated that abnormal IGF-1 signaling may be related to the activity of microglia and astrocytes,and further,abnormal IGF-1 signaling may affect the pathology of AD through the activation of microglia and astrocytes.Insulin-like growth factor binding proteins（IGFBPs）regulate the biological action of IGF-1 by changing the affinity of IGF-1 to its receptor.We selected insulin-like growth factor binding protein 2（IGFBP-2）as the IGF-1 signaling biomarker.The purpose of our study was to investigate the relationship between IGFBP-2 and AD pathology.Method:Our study included 233 participants from the Alzheimer’s Disease Neuroimaging Initiative（ADNI）whose cerebrospinal fluid levels of IGFBP-2,Soluble triggering receptor expressed on myeloid cells 2（sTREM2）,Glial fibrillary acidic protein（GFAP）,and AD core biomarkers(Aβ₄₂,T-tau,and P-tau₁₈₁)were collected and measured at baseline.Based on the classification of AD biomarkers proposed by the National Institute on Aging-Alzheimer’s Association（NIA-AA）,we assigned 233 participants to stage 0(normal levels of Aβ₄₂（A）,P-tau₁₈₁（T）,and T-tau（N）,stage 1(abnormal Aβ₄₂（A）levels,normal P-tau₁₈₁（T）and T-tau（N）levels),stage 2(abnormal Aβ₄₂（A）levels and abnormal P-tau₁₈₁（T）or T-tau（N）levels),Individuals with abnormal P-tau₁₈₁ or T-tau but normal Aβ₄₂ levels were classified as suspected non-Alzheimer’s pathophysiology（SNAP）.The changes of IGFBP-2 levels in different AD pathological stages were investigated by the above four groups,and one-way analysis of variance（ANOVA）or ka-square analysis was used to calculate the differences among the four groups.We performed a multiple linear regression model to evaluate the correlation of cerebrospinal fluid IGFBP-2（independent variable）with sTREM2,GFAP,and AD core biomarkers(Aβ₄₂,T-tau,P-tau₁₈₁),with age,sex,years of education,and the carrier state of APOE as covariables.We also evaluated the correlation among sTREM2,GFAP,and AD core biomarkers.Mediating analyses were used to verify whether the association between CSF IGFBP-2 and AD pathology was mediated by sTREM2 and GFAP,and significance was calculated through 10,000 bootstrapped iterationsResults:A total of 233 participants were included in this study,including 43 in stage 0,33in stage 1,122 in stage 2,and 35 in SNAP.Cerebrospinal fluid IGFBP-2,sTREM2,and GFAP levels were significantly different among the four groups.Multiple linear regression model showed that increased IGFBP-2 levels were correlated with higher levels of GFAP（β=0.005,P<0.001）and sTREM2（β=24.300,P<0.001）.Increased IGFBP-2 levels were associated with higher levels of Aβ₄₂（β=2.417,P=0.015）,higher levels of P-tau₁₈₁（β=0.122,P<0.001）and T-tau（β=1.186,P<0.001）.Mediation analysis showed that the correlation between IGFBP-2 and Aβ₄₂ was partially mediated by sTREM2（β=0.794,95%CI:0.124-1.610,P=0.016）but not by GFAP（β=0.072,P=0.815）.The correlation between IGFBP-2 and T-tau was mediated by sTREM2（β=0.291,95%CI:0.122-0.500,P<0.001）and GFAP（β=0.427,95%CI:0.222-0.680,P<0.001）.Similarly,the relationship between IGFBP-2 and P-tau₁₈₁ was partially mediated by sTREM2（β=0.031,95%CI:0.011-0.060,P<0.001）and GFAP（β=0.044,95%CI:0.022-0.070,P<0.001）Conclusions and Significance:In this study,it was found that cerebrospinal fluid IGFBP-2 was correlated with the pathology of AD,and this relationship was mediated by sTREM2and GFAP in cerebrospinal fluid to a certain degree.These results further demonstrated the correlation between IGF-1 signaling pathway and AD pathology.However,this study only focused on IGFBP-2,and it is necessary to explore other factors in the IGF-1/insulin signaling pathway in the future to reveal the potential mechanism of these factors in the pathogenesis of AD.