Plasma Glial Fibrillary Acidic Protein Levels Differ along the Spectra of Amyloid Burden and Clinical Disease Stage

Background: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-ß (Aß) may shed light on astrocytic changes in aging and Alzheimer's disease (AD). Objective: To examine associations between plasma GFAP and cortical Aß 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 Aß-PET burden. Aß-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 Aß-PET positive, while clinically normal participants (CDR-SB=0) were a mix of Aß-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aß-PET, and clinical severity. Results: In both cohorts, plasma GFAP increased linearly with Aß-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aß-PET burden, the association between Aß and GFAP became curvilinear (inverted U-shape; quadratic model R2 change=0.165, p=0.009), and Aß-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 Aß-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB>4.0) showed a strong, negative association of higher Aß-PET CLs with lower plasma GFAP. Conclusion: The relationship between astrocytic integrity and cortical Aß may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.