Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline

Abstract

Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau PET, MRI scans, plasma GFAP and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at ≥1 year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET and between tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, sex, education, amyloid and APOE status (β = 0.001, P < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (β = 0.006, P < 0.01) and global tau standardized uptake value ratio (β = 4.33, P < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%) and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology.

Keywords: Alzheimer’s disease biomarkers; cognitive decline; glial fibrillary acidic protein; neurofibrillary tau tangles; positron emission tomography.

Figure 1

Distribution of plasma GFAP by AT status and its correlation with AT biomarkers. (A) Box plots containing the distribution of plasma glial fibrillary acidic protein (GFAP) levels by AT status. Boxes represent the interquartile range of values; the horizontal line indicates the median score per group; whiskers expand up to 1.5 times the interquartile range; remaining dots indicate outliers. Coloured circles represent individual values. Significant differences between groups are marked by a horizonal square bracket with respective P-values. (B) A scatter plot showing the correlation between Centiloid and plasma GFAP values. (C) A scatter plot showing the correlation between global tau standardized uptake value ratio (SUVR) and plasma GFAP levels. In both scatter plots (B and C), the solid line represents the linear regression between variables.

Figure 2

Voxel-wise association between tau and GFAP. Association between plasma glial fibrillary acidic protein (GFAP) and tau PET standardized uptake value ratio uptake independently of Centiloid. Statistical parametric maps were investigated at P < 0.001 with family-wise error-corrected at cluster level. Age, sex, years of education and APOE carriership were used as covariates in the model.

Figure 3

Mediation analysis results. Path diagrams indicate whether plasma glial fibrillary acidic protein (GFAP) mediated the association between Centiloid and global tau standardized uptake value ratio (SUVR) (A) or between global tau SUVR and the annual rate of Mini-Mental State Examination (MMSE) change (B), adjusted for age, sex, education, cortical thickness and MMSE scores (A) or Centiloid (B). The direct effect reflects the extent to which global tau SUVR (A) or annual rate of MMSE change (B) changes when baseline Centiloid (A) or global tau SUVR (B) increases by one unit while baseline plasma GFAP remains unaltered. The indirect effect reflects the extent to which global tau SUVR (A) or annual rate of MMSE change (B) changes when baseline Centiloid (A) or global tau SUVR (B) is held constant and plasma GFAP levels change by the amount it would have changed had baseline Centiloid (A) or global tau SUVR (B) increased by one unit. The total effect is the sum of direct and indirect effects. Asterisks mark statistically significant values.