Subjective cognitive complaints are poor predictors of neurodegenerative disease and future dementia. Errors in metacognition, positive or negative differences between actual and perceived performance, may partially explain this. We aimed to assess whether hypothesized indicators of underlying neurodegenerative factors (e.g. hippocampal atrophy) in mild cognitive impairment (MCI) were associated with overestimation of actual cognitive performance, and hypothesized non-degenerative factors (e.g. depression) were associated with underestimation of performance.

Metacognitive error was estimated from paired subjective and objective cognitive assessments using the Multifactorial Memory Questionnaire and Addenbrooke’s Cognitive Examination – Revised, respectively. A normative model was developed with cognitively healthy older adults (n = 36), and applied to individuals with suspected MCI due to Alzheimer’s disease (AD) or MCI with Lewy bodies (total n = 88). Theorized predictors of subjective overestimation or underestimation of performance (metacognitive error) were assessed, including demographics, AD biomarkers, and mental and physical ill health. Metacognitive error was also assessed as a predictor of conversion to dementia.

Underestimation of cognitive function was associated with depressive symptoms, anxiety, and self-reported autonomic symptoms. Overestimation of cognitive function was associated with age, hippocampal atrophy, plasma glial fibrillary acidic protein, and subsequent dementia conversion.

Underestimation of cognitive function may reflect functional cognitive changes linked to mental and physical ill health, while overestimation of function may be a marker of neurodegenerative changes. Quantifying metacognitive error may provide a noninvasive screening tool for progressive MCI, requiring investigation in an independent sample.

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 Aβ42/40, p-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 (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for Aβ42, Aβ40, GFAP and NfL, and incorporated previously-collected p-tau181 from this same cohort.

Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower Aβ42/40 (p = 0.06). GFAP and p-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 (p = 0.011).

Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p-tau181 in distinguishing MCI overall, and its subgroups, from healthy controls.