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

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).

Plasma glial fibrillary acidic protein is an early marker of Aβ pathology in Alzheimer’s disease

“…15 In addition, an association between longitudinal plasma GFAP and conversion to dementia was also found in a prospective clinical cohort, highlighting its potential value as a prognostic tool. 34 In the current study, we extend these previous findings by showing that plasma GFAP is not only elevated in subjects with Aβ pathology but also correlates with continuous Aβ-PET values, even in individuals with normal CSF Aβ42/40 levels. Interestingly, when we conducted our analyses at the voxel-level we found that elevated plasma GFAP was associated with higher Aβ-PET burden in neocortical regions where Aβ accumulation is normally observed in AD both in all CU as well as Aβ-positive CU individuals.…”

Promising Diagnostic Accuracy of Plasma GFAP and NfL Within The AD Continuum

“…Our data encourage the application of a blood-based biomarker model for an outpatient memory clinic setting, with even more promising results for GFAP than NfL for the discrimination of early stages along the AD continuum, whereas NfL might be more helpful in discriminating later stages. This could be in line with data, in which NfL has been reported to be rather a marker for progression of disease, whereas GFAP could be superior in identifying patients at-risk for developing dementia 43 . Our data may support this hypothesis.…”

“…Neuropathological data have shown a close spatial relationship between Ab plaques and reactive astrocytes, which along with microglia, may trigger a pro-in ammatory cascade and eventually lead to neurodegeneration, which in turn activates astrocytes and microglia 41,42 . As a cytoskeletal component of astrocytes, GFAP could serve as a promising biomarker re ecting astrocytic activation and proliferation during the neurodegenerative processes, including AD, particularly in its earliest stages 43,44 . On the other hand, NfL represents a rather unspeci c biomarker for neurodegeneration, as it is released by axonal damage in multiple neurological disorders 45,46 .…”

“…To our knowledge, only few studies have evaluated the combination of GFAP with other biomarkers so far, and presented the utility of plasma GFAP not just in discriminating healthy controls from patients with AD but also in distinguishing Ab + from Ab-individuals [21][22][23] . Furthermore, higher GFAP levels have been associated with an increased risk for future progression to dementia and a steeper cognitive decline 43,49 . Our data encourage the application of a blood-based biomarker model for an outpatient memory clinic setting, with even more promising results for GFAP than NfL for the discrimination of early stages along the AD continuum, whereas NfL might be more helpful in discriminating later stages.…”

Electroencephalography as a Non-Invasive Biomarker of Alzheimer’s Disease: A Forgotten Candidate to Substitute CSF Molecules?

“…Other blood-based proposed biomarkers include plasma neurofilament light [ 27 ] and serum Glial fibrillary acidic protein [ 28 ], which reflect axonal damage and astrocytosis, respectively. Nevertheless, these proteins are not specific to AD, since they can be found in other neurodegenerative diseases, such as Huntington’s disease or frontotemporal dementia [ 29 ], or even in cognitively normal people at risk of dementia [ 30 ].…”