Inge M W Verberk1, Malika B Laarhuis2, Karlijn A van den Bosch2, Jarith L Ebenau2, Mardou van Leeuwenstijn2, Niels D Prins3, Philip Scheltens2, Charlotte E Teunissen4, Wiesje M van der Flier5. 1. Alzheimer Center, Department of Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands. Electronic address: i.verberk@amsterdamumc.nl. 2. Alzheimer Center, Department of Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands. 3. Alzheimer Center, Department of Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; Brain Research Center, Amsterdam, Netherlands. 4. Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands. 5. Alzheimer Center, Department of Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; Department of Epidemiology and Data Science, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
Abstract
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 β42/40, both GFAP (2·6, 1·4-5·0; p=0·0026) and amyloid β42/40 (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 (pfalse 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.
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 β42/40, both GFAP (2·6, 1·4-5·0; p=0·0026) and amyloid β42/40 (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 (pfalse 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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