Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: a prospective memory clinic-based cohort study

Background Serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are putative non-amyloid blood-based biomarkers indicative of ongoing inflammatory and neurodegenerative disease processes. We aimed to assess their prognostic and monitoring value for progression to dementia in individuals presenting at a memory clinic who are cognitively normal. Methods For this prospective cohort study, we included individuals who were cognitively normal from the Amsterdam Dementia Cohort and received screening for dementia at first visit and annual follow-up visits. Participants without a serum sample stored in the Amsterdam Dementia Biobank within 6 months of baseline visit and without a follow-up diagnosis after a minimum of 6 months were excluded. We measured serum GFAP and NfL levels at baseline for all participants and at follow-up for a subset of participants. Using Cox proportional hazard models, we investigated associations of biomarker levels (Z-transformed) with incident dementia (adjusted for age and sex), by entering the markers first separately and then simultaneously, to test independent associations. We also assessed longitudinal performance of the markers on a standardised neuropsychological test battery covering global cognition, memory, language, executive functioning, and attention (adjusted for age, sex, and education). Finally, we evaluated the association of slopes of biomarker levels with incident dementia (adjusted for age and sex). Findings Between July 13, 2001, and Aug 17, 2016, 300 individuals were included in the study. Mean baseline age was 61 years (SD 9), 125 (42%) of participants were women, and mini-mental state examination was 29 (IQR 27–29). Median follow-up time was 3·0 years (IQR 1·9–4·2), with a median of three visits per participant (range 2–12; 1010 total neuropsychological evaluations). During follow-up, 27 (9%) of 300 individuals developed dementia. Both high baseline GFAP (hazard ratio 3·6, 95% CI 2·2–5·7; p<0·0001) and high baseline NfL (1·8, 1·2–2·8; p=0·0037) were associated with increased risk of dementia. When entering both markers simultaneously in the model, only GFAP remained associated with an increased risk of dementia (3·3, 1·9–5·5; p<0·0001). When additionally entering (inverted) plasma amyloid β 42/40 , both GFAP (2·6, 1·4–5·0; p=0·0026) and amyloid β 42/40 (2·1, 1·2–3·6; p=0·0091) were independently associated with incident dementia whereas NfL was not (1·4, 0·8–2·5; p=0·28). Linear mixed models showed that higher baseline GFAP levels were associated with a steeper rate of decline in the domains of memory, attention, and executive functioning (p false discovery rate <0·05), whereas higher NfL levels were not. Repeated serum GFAP and NfL analyses revealed that NfL levels rose more steeply over time in individuals with incident dementia compared with those without (p=0·0006), whereas GFAP levels did not (p=0·074). Interpretation Our results suggest that, while serum NfL seems to have potential as monitoring biomarker, GFAP might be a valuable prognostic biomarker, predicting incident dementia. Funding Alzheimer Nederland, Gieskes Strijbis Fonds.

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