Plasma glial fibrillary acidic protein is an early marker of Aβ pathology in Alzheimer’s disease

Abstract

Although recent clinical trials targeting amyloid in Alzheimers disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid 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 amyloid 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 amyloid-negative cognitively unimpaired individuals, 71 amyloid-positive cognitively unimpaired individuals, 78 amyloid-positive cognitively impaired individuals, 63 amyloid-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal amyloid (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 amyloid-positive groups compared with subjects without amyloid pathology (p<0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-PET signal in all amyloid-positive groups, but also in cognitively normal individuals with normal amyloid values (p<0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-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 amyloid-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 amyloid-PET only in amyloid-positive cognitively impaired individuals (p=0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-PET and cognitive decline, and mediated the effect of amyloid-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid 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 amyloid pathology.

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with β-amyloid-PET, neurodegeneration and cognition

“…These clinical observations fit well with pathology studies that show a gradual increase of GFAP levels in the brain in relation to AD severity 44,45 . Plasma GFAP levels have also been reported to associate with longitudinal cognitive decline and cerebral atrophy, which is confirmed in our study, [46][47][48][49] and higher incident dementia risk 35,42 . Thus, familial, clinical, and population-based studies suggest that increased plasma or serum GFAP levels not only associate with, but also predict, disease progression in AD.…”

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with β-amyloid-PET, neurodegeneration and cognition

“…These clinical observations t well with pathology studies that show a gradual increase of GFAP levels in the brain in relation to AD severity 35,36 . Plasma GFAP levels have also been reported to associate with longitudinal cognitive decline and cerebral atrophy, which is con rmed in our study, [37][38][39][40] and higher incident dementia risk 26,33 . Thus, familial, clinical, and population-based studies suggest that increased plasma or serum GFAP levels not only associate with, but also predict, disease progression in AD.…”

A population‐based meta‐analysis of circulating GFAP for cognition and dementia risk

“…Consistent with our findings, several prior studies have reported negative associations between blood-derived GFAP levels and cognition. [18][19][20]22 A cross-sectional study of 1843 Hispanic and non-Hispanic white participants across the continuum of cognitively intact to AD dementia reported that higher serum GFAP levels were associated with poorer global cognition, learning, and memory. 19 A separate study conducted in 114 older adults with unimpaired cognition, mild cognitive impairment, or AD reported that plasma GFAP levels explained 25% of the variance in memory, as well 10%-15% of the variance in visuospatial, language/semantic knowledge, and executive function domains.…”

“…A prior study of cognitively intact adults with and without elevated amyloid PET burden reported that blood-derived GFAP levels were negatively associated with working memory and executive function, but not with verbal, visual, or episodic memory or global cognition. 21 In addition, unlike many previous studies, 19,20,22,24 our sample was derived from population-based cohorts and did not include individuals with dementia at baseline. The association between cognition and blood-derived GFAP levels may be smaller in the context of normal aging and increase more saliently among those with an underlying neurodegenerative disease process.…”

“…[16][17][18][19][20] Relevant to secondary prevention efforts, plasma GFAP levels have also been found to predict amyloid positivity among cognitively unimpaired adults. [21][22][23][24] Despite these encouraging findings, substantial heterogeneity exists. A recent meta-analysis reported higher CSF GFAP levels in individuals with AD relative to cognitively unimpaired adults.…”