Tracking reactive astrogliosis in autosomal dominant and sporadic Alzheimer’s disease with multi-modal PET and plasma GFAP

BACKGROUND: Plasma assays for the detection of Alzheimer’s disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-β burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer (11)C-Deuterium-L-Deprenyl ((11)C-DED) in a multi-modal PET design in participants with sporadic and Autosomal Dominant Alzheimer’s disease. METHODS: Twenty-four individuals from families with known Autosomal Dominant Alzheimer’s Disease mutations (mutation carriers = 10; non-carriers = 14) and fifteen patients with sporadic Alzheimer’s disease were included. The individuals underwent PET imaging with (11)C-DED, (11)C-PIB and (18)F-FDG, as markers of reactive astrogliosis, amyloid-β deposition, and glucose metabolism, respectively, and plasma sampling for measuring GFAP concentrations. Twenty-one participants from the Autosomal Dominant Alzheimer’s Disease group underwent follow-up plasma sampling and ten of these participants underwent follow-up PET imaging. RESULTS: In mutation carriers, plasma GFAP levels and (11)C-PIB binding increased, while (11)C-DED binding and (18)F-FDG uptake significantly decreased across the estimated years to symptom onset. Cross-sectionally, plasma GFAP demonstrated a negative correlation with (11)C-DED binding in both mutation carriers and patients with sporadic disease. Plasma GFAP indicated cross-sectionally a significant positive correlation with (11)C-PIB binding and a significant negative correlation with (18)F-FDG in the whole sample. The longitudinal levels of (11)C-DED binding showed a significant negative correlation with longitudinal plasma GFAP concentrations over the follow-up interval. CONCLUSIONS: Plasma GFAP concentration and astrocyte (11)C-DED brain binding levels followed divergent trajectories and may reflect different underlying processes. The strong negative association between plasma GFAP and (11)C-DED binding in Autosomal Dominant and sporadic Alzheimer’s disease brains may indicate that if both are markers of reactive astrogliosis, they may detect different states or subtypes of astrogliosis. Increased (11)C-DED brain binding seems to be an earlier phenomenon in Alzheimer’s disease progression than increased plasma GFAP concentration. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-023-00647-y.