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Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression
Open accessAbstract
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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“CSF neurogranin is presumed to measure synaptic degeneration and loss [170,171], and neurofilament light chain [172] is presumed to measure axonal injury.”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [172]
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“Furthermore, several studies describe association between cognitive impairment and increased CSF (Zetterberg et al., 2016) and plasma NFL (Lin et al., 2018) in AD.”
From Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis (2020) · cites this paper as Zetterberg et al., 2016
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Self-citationCSF neurofilament light levels predict hippocampal atrophy in cognitively healthy older adults
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“The only previous study assessing CSF NFL in relation to longitudinal volume change in older adults found that higher NFL levels were associated with deterioration in whole-brain, ventricular and hippocampal volume in MCI patients.(4) However, cross-sectional studies in nondemented adults have been more inconsistent.”
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“NFL is primarily expressed in myelinated largecalibre axons, and leak into CSF in conditions characterised by degeneration in, or injury to, areas of the brain dominated by white matter, such as multiple sclerosis (MS) (8) and vascular dementia (9), but also in some neurodegenerative conditions with preferential corti…”
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Self-citationCSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease
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Self-citationPoly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers
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“However, concentrations of neurofilament light chain in CSF have also been reported to be elevated in other neurological disorders such as Alzheimer disease (AD) (Zetterberg et al., 2016) and Parkinson disease (Bäckström et al., 2015).”
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BackgroundCerebrospinal fluid neurofilament light chain is a marker of aging and white matter damage
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“The levels of neurofilament light chain concentration were also high in AD progression (Zetterberg et al., 2016).”
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“62 In SCZ, elevated NfL levels correlate with worse outcomes, while decreased NfL post-treatment does not relate to antipsychotic dosage.”
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“…is increased in the cerebrospinal fluid (CSF) and blood in several neurodegenerative diseases, including AD (Backstrom et al. 2015; Pijnenburg et al. 2015; Scherling et al. 2014; Novakova et al. 2017; Gaiottino et al. 2013; Hansson et al. 2017; Zetterberg et al. 2016; Mattsson et al. 2017).”
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“A previous report suggests that NEFL might be a good biomarker for neuronal function [45].”
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“…represents a composition of affine and non-linear diffeomorphic transformations Cerebrospinal fluid collection and analysis CSF was collected and assayed as described previously (Starks et al. 2015; E. Portelius et al. 2015; H. Zetterberg et al. 2016) and methods were identical across cohorts.”
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Self-citationBiomarkers of Alzheimer’s disease: Past, present and future clinical use
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Advances in amyloid beta oligomer detection applications in Alzheimer's disease
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Bayoumy, S., Verberk, I. M. W., Vermunt, L., Willemse, E. A. J., den Dulk, B., van der Ploeg, A. T., Pajkrt, D., Nitz, E., van den Hout, J. M. P., van der Post, J., et al. (2024) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2023-1311 · Cited by 44
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Sethi, P., Bhaskar, R., Singh, D. K. K., Gupta, S., Han, S. S., Avinash, D., Abomughaid, M. M., Koul, A., Rani, B., Ghosh, S., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102411 · Cited by 44
Calabresi, P. A., Arnold, D. L., Sangurdekar, D. P., Singh, C. M., Altincatal, A., de Moor, C., Engle, B., Goyal, J., Deykin, A., Szak, S. T., et al. (2020) · Multiple Sclerosis Journal · doi:10.1177/1352458520972573 · Cited by 43
Plasma biomarkers for prognosis of cognitive decline in patients with mild cognitive impairment
Kivisäkk, P., Magdamo, C., Trombetta, B. A., Noori, A., Kuo, Y., Chibnik, L. B., Carlyle, B. C., Serrano‐Pozo, A., Scherzer, C. R., Hyman, B. T., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac155 · Cited by 45
“Plasma levels of Aβ40 and Aβ42 were measured using Euroimmun Beta-Amyloid (1-40) and (1-42) ELISA assays (Lübeck, Germany) performed on a Table 1 Study participant summary statistics Characteristics MCI-stable MCI-progressors Discovery data set Number of participants (N ) 30 30 Age [Mean (SD)] 75.9 (9.1) 78.1 (6.7) Fe…”
MethodInfluentialFrick, E. A., Emilsson, V., Jónmundsson, Þ., Steindorsdottir, A. E., Johnson, E. C. B., Puerta, R., Dammer, E. B., Shantaraman, A., Cano, A. C., Boada, M., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00693-1 · Cited by 47
Alzheimer's disease markers in the aged sheep (Ovis aries)
Reid, S. J., Mckean, N. E., Henty, K., Portelius, E., Blennow, K., Rudiger, S. R., Bawden, C. S., Handley, R. R., Verma, P. J., Faull, R. L. M., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.06.020 · Cited by 42
“Neurofilament light levels in human CSF can also potentially be used as a biomarker of AD progression (Zetterberg et al., 2016), and our results show that neurofilament light can be detected and measured in sheep, and is found at levels comparable to that of humans.”
BackgroundResultInfluentialSelf-citationAlzheimer’s Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint
Alawode, D. O. T., Fox, N. C., Zetterberg, H., & Heslegrave, A. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.837390 · Cited by 41
Self-citationMetabolomic‐guided discovery of Alzheimer's disease biomarkers from body fluid
Ady, C. N. A. E., Lim, S. M., Teh, L. K., Salleh, M. Z., Chin, A., Tan, M. P., Poi, P. J. H., Kamaruzzaman, S. B., Majeed, A. B. A., & Ramasamy, K. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24048 · Cited by 41
Zhao, H., Mo, M., Miao, C., Li, L., Yang, H., Liu, Y., & Yang, G. (2020) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2020.01.006 · Cited by 39
Bridging the Gap Between Fluid Biomarkers for Alzheimer’s Disease, Model Systems, and Patients
Bjorkli, C., Sandvig, A., & Sandvig, I. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00272 · Cited by 41
“Importantly, CSF neurofilament light levels have been shown to be higher in AD (Sjogren et al., 2001; Pijnenburg et al., 2007; Zetterberg et al., 2016; Alcolea et al., 2017; Lista et al., 2017).”
BackgroundPrediction of Outcome After Endovascular Embolectomy in Anterior Circulation Stroke Using Biomarkers
Pujol-Calderón, F., Zetterberg, H., Portelius, E., Hendèn, P. L., Rentzos, A., Karlsson, J.-E., Höglund, K., Blennow, K., & Rosengren, L. (2021) · Translational Stroke Research · doi:10.1007/s12975-021-00905-5 · Cited by 42
Self-citationHalbgebauer, 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) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01122-4 · Cited by 40
Association of neurofilament light chain with renal function: mechanisms and clinical implications
Tang, R., Panizzon, M. S., Elman, J. A., Gillespie, N. A., Hauger, R. L., Rissman, R. A., Lyons, M. J., Neale, M. C., Reynolds, C. A., Franz, C. E., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01134-0 · Cited by 40
“The CSF NfL concentration was measured using a commercially available enzyme-linked immunosorbent assay (ELISA) following the protocol provided by the manufacturer (NFlight; Uman Diagnostics) as described previously [21].”
MethodNanoconstructs as a versatile tool for detection and diagnosis of Alzheimer biomarkers
Gopalan, D., Pandey, A. P., Alex, A. T., Kalthur, G., Pandey, S., Udupa, N., & Mutalik, S. (2020) · Nanotechnology · doi:10.1088/1361-6528/abcdcb · Cited by 42
VALZ‐Pilot: High‐dose valacyclovir treatment in patients with early‐stage Alzheimer's disease
Weidung, B., Hemmingsson, E., Olsson, J., Sundström, T., Blennow, K., Zetterberg, H., Ingelsson, M., Elgh, F., & Lövheim, H. (2022) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12264 · Cited by 40
“42 CSF YKL-40 is a biomarker of neuroinflammation and may be involved in the downregulation of glial phagocytic activities.”
Self-citationXu, W., Han, S., Zhang, C. M., Li, J., Wang, Y., Tan, C., Li, H.-Q., Dong, Q., Mei, C., Tan, L., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb3063 · Cited by 39
The vascular contribution of apolipoprotein E to Alzheimer’s disease
Chen, F., Zhao, J., Meng, F., He, F., Ni, J., & Fu, Y. (2024) · Brain · doi:10.1093/brain/awae156 · Cited by 39
CSF biomarkers in neurodegenerative and vascular dementias
Llorens, F., Schmitz, M., Ferrer, I., & Zerr, I. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.03.003 · Cited by 44
“In this line, association between CSF NF-L levels and AD progression has recently been established (Zetterberg et al., 2015).”
BackgroundSuidan, G. L., Singh, P. K., Patel-Hett, S. R., Chen, Z., Volfson, D., Yamamoto‐Imoto, H., Norris, E. H., Bell, R. D., & Strickland, S. (2018) · Blood Advances · doi:10.1182/bloodadvances.2018017798 · Cited by 39
Allison, S. L., Koscik, R. L., Cary, R. P., Jonaitis, E. M., Rowley, H. A., Chin, N. A., Zetterberg, H., Blennow, K., Carlsson, C. M., Asthana, S., et al. (2019) · NeuroImage Clinical · doi:10.1016/j.nicl.2019.101895 · Cited by 41
“Despite this low level of agreement, results from Mann-Whitney U tests and Cliff's deltas, unadjusted for age, indicated similar performance in terms of differentiating the A-T- CU group from the AD continuum groups (i.e., A+T- CU, A+T+ CU, A+ MCI, and A+ AD).”
BackgroundInfluentialSelf-citationWang, Z., Wang, R., Li, Y., Li, M., Zhang, Y., Jiang, L., Fan, J., Wang, Q., & Yang, D. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.631738 · Cited by 39
“Neurofilament light chain (NfL) is a neuron-specific structural protein (Zetterberg, 2016) that has recently been suggested as a marker of axonal injury and neurodegeneration with potential applications for both patient monitoring and for observational and interventional studies (Tiedt et al.,…”
BackgroundRahimian, P., & He, J. J. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.04.003 · Cited by 39
Tangen, G. G., Nilsson, M. H., Stomrud, E., Palmqvist, S., & Hansson, O. (2022) · Neurology · doi:10.1212/wnl.0000000000201106 · Cited by 39
Alzheimer disease seen through the lens of sex and gender
Castro‐Aldrete, L., Einsiedler, M., Martínková, J., Depypere, H. T., Ang, T. F. A., Mielke, M. M., Sindi, S., Eyre, H. A., Au, R., Dimech, A. S., et al. (2025) · Nature Reviews Neurology · doi:10.1038/s41582-025-01071-0 · Cited by 46
“However, CSF levels of NfL are consistently higher in men than in women across the clinical spectrum from MCI to AD 175,176 .”
Biomarkers: Our Path Towards a Cure for Alzheimer Disease
Tarawneh, R. M. (2020) · Biomarker Insights · doi:10.1177/1177271920976367 · Cited by 42
The Potential of Neurofilament Light as a Biomarker in Alzheimer’s Disease
Xiong, Y.-L., Meng, T., Luo, J., & Zhang, H. (2021) · European Neurology · doi:10.1159/000513008 · Cited by 37
Hong, S., Dobričić, V., Ohlei, O., Bos, I., Vos, S. J. B., Prokopenko, D., Tijms, B. M., Andréasson, U., Blennow, K., Vandenberghe, R. R., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12330 · Cited by 33
Self-citationJensen, C. S., Portelius, E., Høgh, P., Wermuth, L., Blennow, K., Zetterberg, H., Hasselbalch, S. G., & Simonsen, A. H. (2017) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.03.007 · Cited by 36
“Neurofilament light (NFL) is a marker of damage to large-caliber myelinated axons, and elevated CSF levels have been associated with cognitive deterioration and structural changes in the white matter and brain atrophy in patients with AD [10].”
Self-citationNeurofilaments contribution in clinic: state of the art
Delaby, C., Bousiges, O., Bouvier, D., Fillée, C., Fourier, A., Mondésert, E., Nezry, N., Omar, S., Quadrio, I., Rucheton, B., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1034684 · Cited by 38
“Therefore, elevated CSF NfL in the early clinical stages of AD may predict accelerated cognitive decline and conversion to dementia in AD (Zetterberg et al., 2016; Lim et al., 2021).”
BackgroundPlasma phosphorylated tau181 predicts cognitive and functional decline
Tropea, T. F., Waligórska, T., Xie, S. X., Nasrallah, I. M., Cousins, K. A. Q., Trojanowski, J. Q., Grossman, M., Irwin, D. J., Weintraub, D. A., Lee, E. B., et al. (2022) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51695 · Cited by 39
Self-citationIbáñez, L., Liu, M., Beric, A., Timsina, J., Kohlfeld, P., Bergmann, K., Lowery, J., Sykora, N., Montejo, B. S., Brock, W., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14413 · Cited by 42
Cousins, K. A. Q., Phillips, J. S., Irwin, D. J., Lee, E. B., Wolk, D. A., Shaw, L. M. J., Zetterberg, H., Blennow, K., Burke, S., Kinney, N. G., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12233 · Cited by 38
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“Numerous studies support that serum NfL (sNfL) is a sensitive biomarker for acute neuronal injury [8] and chronic neurodegenerative disorders such as Alzheimer’s disease [9], progressive supranuclear palsy [10] Manuscript submitted August 31, 2019, accepted September 9, 2019”
BackgroundMethodSelf-citationTofiq, A., Zetterberg, H., Blennow, K., Basun, H., Cederholm, T., Eriksdotter, M., Irving, G. F., Hjorth, E., Jernerén, F., Schultzberg, M., et al. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210007 · Cited by 38
“Whether these findings are of clinical significance is hard to say, though studies have shown that elevated levels of NfL are associated with cognitive impairment [54,55], a finding also seen regarding YKL-40 [56], the difference being that these studies had longer follow up time, ranging”
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CSF neurogranin or tau distinguish typical and atypical Alzheimer disease
Wellington, H., Paterson, R. W., Gonzalez, A. S., Poole, T., Frost, C. D., Sjöbom, U., Slattery, C. F., Magdalinou, N. K., Lehmann, M., Portelius, E., et al. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.518 · Cited by 34
Self-citation
Metadata
- 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
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2016-01-01
- Volume
- 73
- Issue
- 1
- Pages
- 60
- ISSN
- 2168-6149 (ISSN-L)
- 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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