Evaluation of the association between circulatory markers of neuroinflammation and Alzheimer’s disease pathology

Abstract

AbstractBackgroundIncreasing evidence suggests that neuroinflammation and astrogliosis have a prominent role in the spread of pathology and the development of cognitive impairment in Alzheimer’s disease (AD). Circulating plasma markers of neuroinflammation, such as the glial fibrillary acid protein (GFAP), have recently become available, and early observations suggest a robust association with brain pathology. Positron emission tomography (PET) is a molecular imaging technique that allows visualisation and quantification of AD pathology in vivo. The aim of this study was to evaluate the association between GFAP and AD pathology, and its interaction with cognitive decline.Method121 subjects from the Geneva Memory Centre underwent amyloid and tau PET, blood collection, and mini‐mental state examination (MMSE). Amyloid uptake was calculated as centiloid whereas tau was quantified as standardised uptake value ratio. Association of centiloid and tau with GFAP was assessed using a multivariate linear regression model, corrected for age, gender, and MMSE. Mediation analysis described the mediating effect of GFAP on the association between centiloid and tau. Ninety‐four subjects had a follow‐up MMSE after at least 12 months. Linear regression was used to assess the effect of GFAP on the annual rate of change of MMSE (corrected for centiloid, global tau, age, and gender). Mediation analysis was used to test whether the relationship between rate of MMSE change and tau could be explained by a mediation of GFAP.ResultThe mean (SD) age of the participants was 72.6 (7.6) years, and 61 of 121 subjects were men. GFAP was significantly associated with increased tau, but not with centiloid. GFAP partially mediated the effect of centiloid on global tau (mediated proportion = 14%, p = 0.03). The rate of MMSE change was significantly associated with GFAP, and global tau, but not with centiloid. Moreover, GFAP partially mediated the effect between global tau SUVR and change of MMSE scores (52%, p<0.01).ConclusionElevated GFAP is associated with tau. GFAP also partially explains the effect of amyloid pathology on tau accumulation and of tau pathology on subsequent cognitive decline. These results support neuroinflammation and astrogliosis as a relevant contributor to AD pathology, which can be monitored in blood.