Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage1

Abstract

Background: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer’s disease (AD). Objective: To examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum. Methods: We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity. Results: In both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5–4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP. Conclusion: The relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.

Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment

“…However, the results from previous studies with amyloid-PET imaging suggest that as the Aβ load increases in brain along the course of disease, astrogliosis decreases [ 9 , 11 ]. A similar dynamic association was observed in a recent cross-sectional study on plasma GFAP, where linear positive associations between brain Aβ load measured with amyloid-PET were observed in subjects at earlier stages of disease and diverged in more severe disease stages [ 25 ]. Our cohort had an adequate follow-up time (4.7 years on average); however, we cannot exclude that at a longer follow-up a similar association could be observed.…”

“…GFAP has also been recently measured in plasma and serum, where it was found increased in different neurological conditions, including AD [16][17][18][19][20][21][22][23][24]. Different studies have shown that higher concentrations of plasma GFAP were associated to amyloid-PET positivity and worse outcomes in global cognition [22,[24][25][26][27]. Even though previous studies suggest that blood GFAP levels are elevated in AD and can identify an amyloid-PET positive status, only one study has measured GFAP in cognitively normal subjects followed over time for conversion to dementia (of any kind) [27].…”

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

“…Although emerging evidence suggests that inflammation has a causal role in AD, [11][12][13][14][15][16][17][18] the detection of inflammatory markers has not yet been established as a valuable method for the early diagnosis and monitoring of AD patients. 1 Our findings show that plasma GFAP holds great potential as an early and specific marker of Aβ deposition even during the earliest stages of AD.…”

“…In particular, the recent assays that allow measuring the concentrations of GFAP in the blood have already demonstrated the potential of plasma GFAP in distinguishing different stages of AD and detecting Aβ positivity on positron emission tomography (PET). [10][11][12][13][14][15][16][17][18] However, no study has yet assessed whether plasma GFAP is also associated with tau-PET burden. Moreover, to this date, it is not known whether astrocytosis is independently related to Aβ or tau pathology, respectively, in vivo.…”

Plasma Glial Fibrillary Acidic Protein Detects Alzheimer Pathology and Predicts Future Conversion to Alzheimer Dementia in Patients With Mild Cognitive Impairment

“…GFAP has also been recently measured in plasma and serum, where it was found increased in different neurological conditions, including AD (16)(17)(18)(19)(20)(21)(22)(23)(24). Increase of plasma GFAP in AD patients was associated to amyloid-PET positivity and worse outcomes in global cognition (22,24,25). Even though previous studies suggest that blood GFAP levels are elevated in AD and can identify an amyloid-PET positive status, no studies have been done investigating whether plasma GFAP can predict future conversion to AD dementia in patients with mild cognitive impairment (MCI).…”