Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma A 42/40, -tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another. Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset ( = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for A 42, A 40, GFAP and NfL, and incorporated previously-collected -tau181 from this same cohort. Probable MCI-LB had elevated GFAP ( < 0.001) and NfL ( = 0.012) relative to controls, but not significantly lower A 42/40 ( = 0.06). GFAP and -tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time ( = 0.011). Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to -tau181 in distinguishing MCI overall, and its subgroups, from healthy controls.