Plasma glial fibrillary acidic protein is an early marker of amyloid pathology in Alzheimer's disease

Although recent clinical trials targeting amyloid-{beta} (A{beta}) in Alzheimers disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with A{beta} 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 AD. However, to this date, no studies have assessed whether astrocytosis is independently related to A{beta} or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 A{beta}-negative cognitively unimpaired individuals, 71 A{beta}-positive cognitively unimpaired individuals, 78 A{beta}-positive cognitively impaired individuals, 63 A{beta}-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal A{beta} (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all A{beta}-positive groups compared with subjects without A{beta} pathology (p<0.01). In addition, there were significant associations between plasma GFAP with higher A{beta}-PET signal in all A{beta}-positive groups, but also in cognitively normal individuals with normal A{beta} values (p<0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict A{beta}-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, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for A{beta}-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p<0.05) and correlated with A{beta}-PET only in A{beta}-positive cognitively impaired individuals (p=0.005). Finally, plasma GFAP was associated with both longitudinal A{beta}-PET and cognitive decline, and mediated the effect of A{beta}-PET on tau-PET burden, suggesting that astrocytosis secondary to A{beta} aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain A{beta} pathology but not tau aggregation, even in cognitively normal individuals with a normal A{beta} status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to A{beta} pathology.