Cited by 490Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression

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Zetterberg, Henrik, Skillbäck, Tobias, Mattsson, Niklas, Trojanowski, John Q., Portelius, Erik, Shaw, Leslie M., Weiner, Michael W., Blennow, Kaj, for the Alzheimer’s Disease Neuroimaging Initiative·2016·JAMA Neurology

DOI 10.1001/jamaneurol.2015.3037PMC PMC5624219

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Abstract

IMPORTANCE: The extent to which large-caliber axonal degeneration contributes to Alzheimer disease (AD) progression is unknown. Cerebrospinal fluid (CSF) neurofilament light (NFL) concentration is a general marker of damage to large-caliber myelinated axons. OBJECTIVE: To test whether CSF NFL concentration is associated with cognitive decline and imaging evidence of neurodegeneration and white matter change in AD. DESIGN, SETTING, AND PARTICIPANTS: A commercially available immunoassay was used to analyze CSF NFL concentration in a cohort of patients with AD (n = 95) or mild cognitive impairment (MCI) (n = 192) and in cognitively normal individuals (n = 110) from the Alzheimer's Disease Neuroimaging Initiative. The study dates were January 2005 to December 2007. The NFL analysis was performed in November 2014. MAIN OUTCOMES AND MEASURES: Correlation was investigated among baseline CSF NFL concentration and longitudinal cognitive impairment, white matter change, and regional brain atrophy within each diagnostic group. RESULTS: Cerebrospinal fluid NFL concentration (median [interquartile range]) was higher in the AD dementia group (1479 [1134-1842] pg/mL), stable MCI group (no progression to AD during follow-up; 1182 [923-1687] pg/mL), and progressive MCI group (MCI with progression to AD dementia during follow-up; 1336 [1061-1693] pg/mL) compared with control participants (1047 [809-1265] pg/mL) (P < .001 for all) and in the AD dementia group compared with the stable MCI group (P = .01). In the MCI group, a higher CSF NFL concentration was associated with faster brain atrophy over time as measured by changes in whole-brain volume (β = -4177, P = .003), ventricular volume (β = 1835, P < .001), and hippocampus volume (β = -54.22, P < .001); faster disease progression as reflected by decreased Mini-Mental State Examination scores (β = -1.077, P < .001) and increased Alzheimer Disease Assessment Scale cognitive subscale scores (β = 2.30, P < .001); and faster white matter intensity change (β = 598.7, P < .001). CONCLUSIONS AND RELEVANCE: Cerebrospinal fluid NFL concentration is increased by the early clinical stage of AD and is associated with cognitive deterioration and structural brain changes over time. This finding corroborates the contention that degeneration of large-caliber axons is an important feature of AD neurodegeneration.

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Additional file 9 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Remnestål, J., Bergström, S., Olofsson, J., Sjöstedt, E., Uhlén, M., Blennow, K., Zetterberg, H., Zettergren, A., Kern, S., Skoog, I. G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14150870
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Additional file 6 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
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Additional file 3 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Remnestål, J., Bergström, S., Olofsson, J., Sjöstedt, E., Uhlén, M., Blennow, K., Zetterberg, H., Zettergren, A., Kern, S., Skoog, I. G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14150852
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Additional file 4 of Optimized sample preparation and data analysis for TMT proteomic analysis of cerebrospinal fluid applied to the identification of Alzheimer’s disease biomarkers
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Additional file 10 of Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
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Additional file 5 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Remnestål, J., Bergström, S., Olofsson, J., Sjöstedt, E., Uhlén, M., Blennow, K., Zetterberg, H., Zettergren, A., Kern, S., Skoog, I. G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14150858
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Additional file 10 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Remnestål, J., Bergström, S., Olofsson, J., Sjöstedt, E., Uhlén, M., Blennow, K., Zetterberg, H., Zettergren, A., Kern, S., Skoog, I. G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14150843
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Additional file 4 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Remnestål, J., Bergström, S., Olofsson, J., Sjöstedt, E., Uhlén, M., Blennow, K., Zetterberg, H., Zettergren, A., Kern, S., Skoog, I. G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14150855
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Additional file 2 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Remnestål, J., Bergström, S., Olofsson, J., Sjöstedt, E., Uhlén, M., Blennow, K., Zetterberg, H., Zettergren, A., Kern, S., Skoog, I. G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14150849
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Additional file 3 of Optimized sample preparation and data analysis for TMT proteomic analysis of cerebrospinal fluid applied to the identification of Alzheimer’s disease biomarkers
Weiner, S., Sauer, M., Visser, P. J., Tijms, B. M., Vorontsov, E. A., Blennow, K., Zetterberg, H., & Gobom, J. (2022) · Figshare · doi:10.6084/m9.figshare.19768006
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Additional file 4 of Utilization of fluid-based biomarkers as endpoints in disease-modifying clinical trials for Alzheimer’s disease: a systematic review
Oosthoek, M., Vermunt, L., de Wilde, A., Bongers, B., Antwi‐Berko, D., Scheltens, P., van Bokhoven, P., Vijverberg, E. G. B., & Teunissen, C. E. (2024) · Figshare · doi:10.6084/m9.figshare.26713496
Additional file 2 of Optimized sample preparation and data analysis for TMT proteomic analysis of cerebrospinal fluid applied to the identification of Alzheimer’s disease biomarkers
Weiner, S., Sauer, M., Visser, P. J., Tijms, B. M., Vorontsov, E. A., Blennow, K., Zetterberg, H., & Gobom, J. (2022) · Figshare · doi:10.6084/m9.figshare.19768003
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Additional file 3 of Utilization of fluid-based biomarkers as endpoints in disease-modifying clinical trials for Alzheimer’s disease: a systematic review
Oosthoek, M., Vermunt, L., de Wilde, A., Bongers, B., Antwi‐Berko, D., Scheltens, P., van Bokhoven, P., Vijverberg, E. G. B., & Teunissen, C. E. (2024) · Figshare · doi:10.6084/m9.figshare.26713493
Additional file 9 of Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
Xia, D., Lianoglou, S., Sandmann, T., Calvert, M., Suh, J. H., Thomsen, E. R., Dugas, J. C., Pizzo, M. E., DeVos, S. L., Earr, T., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20056422
Additional file 1 of Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men
Tang, R., Buchholz, E. J., Dale, A. M., Rissman, R. A., Fennema‐Notestine, C., Gillespie, N. A., Hagler, D. J., Lyons, M. J., Neale, M. C., Panizzon, M. S., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25698219
Additional file 7 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Remnestål, J., Bergström, S., Olofsson, J., Sjöstedt, E., Uhlén, M., Blennow, K., Zetterberg, H., Zettergren, A., Kern, S., Skoog, I. G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14150864
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Additional file 1 of Visinin-like protein 1 levels in blood and CSF as emerging markers for Alzheimer’s and other neurodegenerative diseases
Halbgebauer, S., Steinacker, P., Riedel, D., Oeckl, P., Anderl-Straub, S., Lombardi, J., Arnim, C. A. F. V., Nagl, M., Giese, A., Ludolph, A. C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21622142
Additional file 8 of Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Remnestål, J., Bergström, S., Olofsson, J., Sjöstedt, E., Uhlén, M., Blennow, K., Zetterberg, H., Zettergren, A., Kern, S., Skoog, I. G., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14150867
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Additional file 2 of Utilization of fluid-based biomarkers as endpoints in disease-modifying clinical trials for Alzheimer’s disease: a systematic review
Oosthoek, M., Vermunt, L., de Wilde, A., Bongers, B., Antwi‐Berko, D., Scheltens, P., van Bokhoven, P., Vijverberg, E. G. B., & Teunissen, C. E. (2024) · Figshare · doi:10.6084/m9.figshare.26713490
Cortical asymmetry in autosomal dominant Alzheimer’s disease progression
Pérez‐Millan, A., Falgàs, N., Bosch, B., Borrego‐Écija, S., Antonell, A., Fernández‐Villullas, G., Esteller, D., Tort‐Merino, A., Bargalló, N., Balasa, M., et al. (2025) · Brain Communications · doi:10.1093/braincomms/fcaf488 · Cited by 1
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Xu, J., Chen, H., Wang, Y., Hu, Z., Ke, Z., Huang, L., Mo, Y., Yang, D., Mao, C., Chen, Y., et al. (2026) · Brain Communications · doi:10.1093/braincomms/fcag080 · Cited by 1
“52,53 The Vanderbilt Memory & Aging Project found that NfL was negatively associated with FA and positively associated with MD, axial diffusivity and radial diffusivity.”
Vieillissement et maladies neurodégénératives : nouvelles contraintes apportées par la métallomique
Sauzéat, L. (2018) · theses.fr (ABES) · doi:10.70675/6f22af22z8cfcz4a9fzb647zf065e4131641
Are Lewy body dementia and Parkinson’s disease dementia being the same thing, or are they different: the role of neurochemical biomarkers
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Serum Neurofilament Light Chain Predicts Stroke Outcome and is a Potential Marker for Treatment Effects of Neural Stem Cell-derived Extracellular Vesicles in a Rat Stroke Model
Cannon, M. K., Fojtik, A., White, C. M., Swetenburg, R. L., Stice, S. L., Savitz, S. I., & Baker, E. W. (2026) · Translational Stroke Research · doi:10.1007/s12975-026-01445-6
“In addition, ICAM-1 plays a key role in blood–brain barrier disruption and leukocyte infiltration, supporting its rele - vance as a candidate biomarker given our data showing that NSC EV treatment mitigates hemorrhagic transformation in a pig stroke model [5 ].”
Clinical and biological relevance of objectively-defined subtle cognitive decline in Alzheimer’s disease: a narrative review of neuroimaging, biomarker, and clinical progression studies
Gonzalez, A. I., Martinez, J. E., Giudicessi, A., Rowe, M., Ku, V., Tristão‐Pereira, C., He, B., Malotaux, V., & Quiroz, Y. T. (2026) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2026.100604
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Relationships of CSF biomarkers to cortical atrophy in early‐onset Alzheimer's disease
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Treatment response biomarkers in early Alzheimer’s disease: longitudinal trajectories, sample size estimates, and the impact of progression variabilityPreprint
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Amyloid, p‐tau, neurofilament light, and α‐synuclein cerebrospinal fluid biomarkers across Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease
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“33,34 It must be noted that our PD group was on average younger, mostly cognitively unimpaired, and with mild motor deficits.”
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Authors: Zetterberg, H., Skillbäck, T., Mattsson, N., Trojanowski, J. Q., Portelius, E., Shaw, L. M., Weiner, M. W., Blennow, K., & Initiative, F. T. A. D. N.
Affiliations: UCL Queen Square Institute of Neurology (GB)
University of Gothenburg (SE)
University of California, San Francisco (US)
University of Pennsylvania (US)
Corresponding author: Zetterberg, Henrik
ORCID: Zetterberg, Henrik
Skillbäck, Tobias
Mattsson, Niklas
Trojanowski, John Q.
Portelius, Erik
Shaw, Leslie M.
Weiner, Michael W.
Blennow, Kaj
Venue: JAMA Neurology
Publisher: American Medical Association (AMA)
Published: 2016-01-01
Volume: 73
Issue: 1
Pages: 60
ISSN: 2168-6149 (ISSN-L)
DOI: 10.1001/jamaneurol.2015.3037
PMC: PMC5624219
OpenAlex: W1934117767
Cited by: 487
References: 31
Citations by year: 2026: 20 · 2025: 38 · 2024: 62 · 2023: 42 · 2022: 65 · 2021: 60 · 2020: 62 · 2019: 41 · 2018: 48 · 2017: 35 · 2016: 14
FWCI: 26.27
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: JAMA Neurology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: U.S. Department of Defense (U01 AG024904, AG024904)
Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-)
National Institutes of Health (5u01ag024904-10, W81XWH-12-2-0012, U01-AG024904, AG024904)
Canadian Institutes of Health Research
National Institute on Aging (U01-AG-024904, P30AG010129, K01AG030514, P30AG013846, U24AG021886)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: neurofilament light chain, cerebrospinal fluid biomarkers, mild cognitive impairment, cognitive decline, axonal degeneration, brain atrophy, hippocampal volume, ventriculomegaly, neurodegeneration, Alzheimer's Disease Neuroimaging Initiative, biomarker validation, white matter hyperintensities, amyloid PET, tau PET
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Female, Follow-Up Studies, Humans, Male, Cohort Studies, Biomarkers, Neurofilament Proteins, Disease Progression, Cognitive Dysfunction

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Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression

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