Changes in plasma biomarker levels are predictive of amyloid pathology and memory decline in cognitively unimpaired individuals

Abstract Background Plasma levels of amyloid‐β 1‐42/1‐40 , and glial fibrillary acidic protein (GFAP) have demonstrated predictive potential for amyloid pathology in the early stages of Alzheimer’s disease (AD) development. Utilizing baseline and up to 6‐year follow‐up plasma, positron emission tomography (PET) and cognitive data from cognitively unimpaired individuals, we here aim to test whether early changes in plasma biomarker levels associate with change in amyloid status and cognitive decline. Methods From the EMIF‐AD PreclinAD study we selected individuals with normal cognition and longitudinal plasma, PET and cognitive data available (n baseline =200, table 1). Amyloid‐status was determined using visual assessment of dynamic [ 18 F]flutemetamol‐PET scans. Plasma levels of amyloid‐β1‐40, amyloid‐β1‐42, neurofilament light (NfL), and GFAP were measured using the neurology 4‐plex E Simoa assay (Quanterix). Linear mixed models were applied to examine longitudinal changes in plasma biomarker levels, and their association with longitudinal changes in amyloid‐status and cognition. Results At baseline 13.3%, and at 4‐year follow‐up 25.9% of participants were amyloid‐positive. Twenty‐one participants converted from a negative to positive amyloid‐status. At baseline, GFAP levels were higher and amyloid‐β 1‐42/1‐40 lower in amyloid‐positive compared to negative individuals (β(SE)=0.43(0.14), β(SE)=‐0.75(0.21), p<0.005, respectively). In the total cohort, plasma levels of GFAP and NfL increased over time, whereas amyloid‐β 1‐42/1‐40 remained stable (Figure 1). Although overall stable, plasma amyloid‐β 1‐42/1‐40 decreased in participants that converted from a negative to positive amyloid‐status over time (β(SE)=‐0.04(0.02), p=0.02). Alongside, an increase in GFAP levels was observed in participants that converted from a negative to positive amyloid‐status compared to stable negative participants (Figure 1). No group differences were observed for NfL. A longitudinal increase in GFAP levels was associated with memory decline in stable amyloid positive individuals (GFAP*time*amyloid‐group status: β(SE)=‐0.09(0.02), p<0.001, Figure 2). Conclusions Early changes in plasma GFAP and amyloid‐β 1‐42/1‐40 are associated with changes in amyloid‐status in cognitively unimpaired individuals. Further, increases in plasma GFAP levels over time are predictive of future memory decline in amyloid‐positive individuals. These results support the potential of plasma GFAP and, to a lesser extent, amyloid‐β 1‐42/1‐40 as diagnostic and prognostic markers for AD in early stages of disease development.