Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer’s disease

Abstract

Although recent clinical trials targeting amyloid-β in Alzheimer’s disease have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid-β metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in Alzheimer’s disease. However, so far, no studies have assessed whether astrocytosis is independently related to either amyloid-β or tau pathology in vivo.

To address this question, we determined the levels of the astrocytic marker GFAP in plasma and CSF of 217 amyloid-β-negative cognitively unimpaired individuals, 71 amyloid-β-positive cognitively unimpaired individuals, 78 amyloid-β-positive cognitively impaired individuals, 63 amyloid-β-negative cognitively impaired individuals and 75 patients with a non-Alzheimer’s disease neurodegenerative disorder from the Swedish BioFINDER-2 study. Participants underwent longitudinal amyloid-β ( ¹⁸F-flutemetamol) and tau ( ¹⁸F-RO948) PET as well as cognitive testing.

We found that plasma GFAP concentration was significantly increased in all amyloid-β-positive groups compared with participants without amyloid-β pathology ( P < 0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-β-PET signal in all amyloid-β-positive groups, but also in cognitively normal individuals with normal amyloid-β values ( P < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-β-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, soluble TREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-β-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-Alzheimer’s disease patients compared to other groups ( P < 0.05) and correlated with amyloid-β-PET only in amyloid-β-positive cognitively impaired individuals ( P = 0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-β-PET and cognitive decline, and mediated the effect of amyloid-β-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid-β aggregation might promote tau accumulation.

Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid-β pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid-β status. This suggests that plasma GFAP should be incorporated in current hypothetical models of Alzheimer’s disease pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid-β pathology.

Abstract

Pereira et al. show that plasma GFAP is an early and independent marker of astrocytosis associated with Aβ pathology. Plasma GFAP correlated with cognitive decline and mediated the effect of Aβ-PET on tau-PET burden, suggesting that astrocytosis secondary to Aβ aggregation may promote tau accumulation.