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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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“Robust evidence suggests that NfL levels in CSF are elevated in AD patients, and higher levels are associated with worse disease severity, cognitive decline, and brain atrophy [62].”
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“Serum neurofilament light chain (NfL) also may be useful for discriminating between lvPPA and nonlvPPA with 81% sensitivity and 67% specificity (22), and others have shown elevated NfL in svPPA and naPPA relative to a small number of lvPPA (25) [also see (31)], although others have found CSF NfL elevated in AD (32, 33…”
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Clinical significance of plasma candidate biomarkers of Alzheimer’s Disease
Lewczuk, P., Łukaszewicz‐Zając, M., Kornhuber, J., & Mroczko, B. (2024) · Neurologia i Neurochirurgia Polska · doi:10.5603/pjnns.100675 · Cited by 7
Li, W., Sun, F., Guo, X., Hu, Y., Ding, S., Ding, M., Song, M., Shao, M., Yang, Y., Guo, W., et al. (2020) · Physiology & Behavior · doi:10.1016/j.physbeh.2020.112805 · Cited by 6
Walia, N., Eratne, D., Loi, S. M., Li, Q.-X., Varghese, S., Malpas, C. B., Walterfang, M., Evans, A. H., Parker, S., Collins, S. J., et al. (2021) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2021.120088 · Cited by 6
Chong, J. S. X., Tan, Y. J., Koh, A. J., Ting, S. K. S., Kandiah, N., Ng, A. S. L., & Zhou, J. H. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231251 · Cited by 6
Olsson, B., Schott, J. M., Blennow, K., & Zetterberg, H. (2017) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2017.1341311 · Cited by 7
Self-citationMao, C., Sha, L., Li, J., Huang, X., Chu, S., Lei, D., Wang, J., Dong, L., Liu, C., Xu, Q., et al. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210344 · Cited by 6
Shir, D., Mielke, M. M., Hofrenning, E. I., Lesnick, T. G., Knopman, D. S., Petersen, R. C., Jack, C. R., Algeciras‐Schimnich, A., Vemuri, P., & Graff‐Radford, J. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221015 · Cited by 6
Salvadó, G., Ossenkoppele, R., Ashton, N. J., Beach, T. G., Serrano, G. E., Zetterberg, H., Mattsson, N., Janelidze, S., Blennow, K., & Hansson, O. (2022) · medRxiv · doi:10.1101/2022.08.22.22279052 · Cited by 6
Self-citationProteomics for Target Identification in Psychiatric and Neurodegenerative Disorders
Antunes, A. S. L. M., de Almeida, V., Crunfli, F., Carregari, V. C., & Martins‐de‐Souza, D. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-55035-6_17 · Cited by 5
Gleerup, H. S., Simonsen, A. H., & Høgh, P. (2022) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-210047 · Cited by 5
“A plethora of recent studies have shown that NfL in CSF [6, 7] and blood [8, 9] is robustly increased in AD, but also in many other neurodegenerative disorders and acute neurological disorders [10, 11], making NfL a promising biomarker for the diagnosis of neurodegenerative dementias.”
BackgroundValidity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure
Gifford, K. A., Liu, D., Neal, J. E., Acosta, L. M. Y., Bell, S. P., Wiggins, M. E., Wisniewski, K. M., Godfrey, M., Logan, L. A., Hohman, T. J., et al. (2018) · Assessment · doi:10.1177/1073191118773870 · Cited by 5
“…volume on brain MRI, inferior lateral ventricle volume on brain MRI, and CSF tau; Mandecka et al., 2016; Murphy et al., 2010; Wolk & Dickerson, 2011) and white matter disease (white matter hyperintensities (WMH) on brain MRI and CSF neurofilament light; Lee et al., 2016; Zetterberg et al., 2016).”
BackgroundSelf-citationWang, S., Li, T., Zhao, B., Dai, W., Yao, Y., Li, C., Li, T., Hongtu Zhu, B., & Zhang, H. (2023) · Genome Research · doi:10.1101/gr.277905.123 · Cited by 5
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“26 In this study we developed a quantitative and highly sensitive immunoassay to measure NfM levels in CSF and subsequently utilise it for the analysis of NfM in the CSF of patients with neurological disorders, including ALS, AD, FTD, and LBD, alongside control cohorts.”
InfluentialDelva, A., Zatti, C., Pelletier, A., Montplaisir, J. Y., Gagnon, J., Kollmorgen, G., Kam‐Thong, T., Kustermann, T., Machado, V., & Postuma, R. B. (2025) · Movement Disorders · doi:10.1002/mds.70016 · Cited by 4
Virga, G., Marco, B., Blandino, V., & Piccoli, T. (2025) · Brain Sciences · doi:10.3390/brainsci15090924 · Cited by 4
“In AD, both CSF and plasma levels of NfL are elevated even in early stages and correlate with clinical severity and disease progression rates [22–24].”
Visual Functions Are Associated with Biomarker Changes in Alzheimer’s Disease
Memon, A., Initiative, A. D. N., Moore, J. A., Kang, C., Ismail, Z., & Forkert, N. D. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231084 · Cited by 4
Tang, Y., Yang, C., Wang, Y., Zhang, Y., Xin, J., Zhang, H., & Xie, H. (2024) · Cerebral Cortex · doi:10.1093/cercor/bhae393 · Cited by 4
Drug Development in Alzheimer’s Disease—The Role of Default Mode Network Assessment in Phase II
Cummings, J. L., Zhong, K., Cordes, D., & Global Alzheimer’s Platform, W. (2017) · US Endocrinology · doi:10.17925/use.2017.13.02.67 · Cited by 4
Fluid Biomarkers in Clinical Trials for Alzheimer’s Disease: Current and Future Application
Yang, J., Jia, L., Li, Y., Qiu, Q., Quan, M., & Jia, J. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201068 · Cited by 4
Biomarkers of Alzheimer’s disease
Bos (2018) · Research Publications (Maastricht University) · doi:10.26481/dis.20181012ib · Cited by 4
Tropea, T. F., Waligórska, T., Xie, S. X., Nasralah, I. M., Cousins, K. A. Q., Trojanowski, J. Q., Grossman, M., Irwin, D. J., Weintraub, D. A., Lee, E. B., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4007185 · Cited by 4
Self-citationBateman, R. J., Li, Y., McDade, E., Guerra, J. J. L., Clifford, D. B., Atri, A., Mills, S. L., Santacruz, A. M., Wang, G., Supnet, C. B., et al. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4906344 · Cited by 4
Brain white matter damage biomarkers
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Ng, B., Kodosaki, E., Veleva, E., Keshavan, A., Schott, J. M., Heslegrave, A., Fox, N. C., & Zetterberg, H. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71082 · Cited by 3
“We confirmed that elevated MMP-10 and NfL levels are associated with worse cognitive performance as previously reported 14,24 and further revealed that this relationship is AD-specific.”
Self-citationRichter, G., Kirsebom, B., Jarholm, J. A., Pålhaugen, L., Gísladóttir, B., Aarsland, D., Grøntvedt, G. R., Skogseth, R. E., Waterloo, K. K., Fladby, T., et al. (2025) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2025.07.005 · Cited by 3
Xia, W., Xu, C., Xiao, Z., Zhou, X., Zhao, Q., Ding, D., & Deng, W. (2026) · Psychological Medicine · doi:10.1017/s0033291725103115 · Cited by 3
“…of NfL correlate with accelerated cognitive decline, white matter lesions, and increased brain atrophy in participants with AD dementia, indicating that degeneration of large-caliber axons is an important element of disease progression in AD (Salwierz et al., 2024; Zetterberg et al., 2016).”
Dementia with Lewy bodies – a clinicopathological update
Bencze, J., Seo, W., Hye, A., Aarsland, D., & Hortobágyi, T. (2019) · Free Neuropathology · doi:10.17879/freeneuropathology-2020-2613 · Cited by 4
Moore, E. E., Khan, O. A., Shashikumar, N., Pechman, K. R., Liu, D., Bell, S. P., Nair, S., Terry, J. G., Gifford, K. A., Anderson, A. W., et al. (2021) · Stroke · doi:10.1161/strokeaha.121.034349 · Cited by 3
“25 Commercially available enzyme-linked immunosorbent assays were used to measure NFL (UmanDiagnostics), total-tau (INNOTEST hTAU), and Aβ (INNOTEST β-AMYLOID[1-42]).”
MethodSelf-citationBiomarkers for Alzheimer's Disease – An Overview
Tyagi, U., Tripathy, D. B., Gupta, A., Bisht, K., & Nain, A. (2024) · Macromolecular Symposia · doi:10.1002/masy.202200218 · Cited by 3
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Rådestig, M. A., Skoog, J., Zetterberg, H., Skillbäck, T. B., Zettergren, A., Sterner, T. R., Fässberg, M. M., Sacuiu, S. F., Wærn, M., Wetterberg, H., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-220452 · Cited by 3
Self-citationNew cerebrospinal fluid biomarkers in Alzheimer’s disease
Burchell, J. T., & Panegyres, P. K. (2017) · Future Neurology · doi:10.2217/fnl-2017-0009 · Cited by 3
Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis
Al-Amin, M. M., Grandjean, J., Klohs, J., & Kim, J. (2020) · doi:10.1101/2020.04.27.064634 · Cited by 2
“The concentrations of NFL is increased both in the plasma (Lin et al., 2018) and CSF (Jin et al., 2019, Zetterberg et al., 2016) in AD.”
BackgroundInfluentialSerum proteomics reveals APOE dependent and independent protein signatures in Alzheimer’s disease
Frick, E. A., Emilsson, V., Jonmundsson, T., Steindorsdottir, A. E., Johnson, E. C. B., Puerta, R., Dammer, E. B., Shantaraman, A., Cano, A., Boada, M., et al. (2023) · doi:10.1101/2023.11.08.23298251 · Cited by 3
Agmon, G., Cho, S., Ash, S., Cousins, K. A. Q., Blennow, K., Zetterberg, H., Shaw, L. M. J., Pradhan, S., Kim, Y. D., Liberman, M., et al. (2025) · Aphasiology · doi:10.1080/02687038.2025.2462282 · Cited by 2
“Seven samples were analyzed using the enzyme-linked immunosorbent assay (ELISA) of UmanDiagnostics (Umea, Sweden) (Zetterberg et al., 2016) while 18 were analyzed using the single-molecule array (SIMOA) from Quanterix (Billerica, MA) (Aamodt et al., 2021) and for 3 samples both assays were available.”
Self-citationMohammed, S. N., Direksunthorn, T., Zwamel, A. H., Uthirapathy, S., Ballal, S., Kalia, R., Arya, R., Naidu, K. S., Ahmad, I. S., & Ahmed, J. K. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05338-x · Cited by 3
“Furthermore, CSF neurofilament (NfL) concentrations, which are associated with the severity of neurodegeneration, were higher in men at different stages of AD [52], although plasma and serum NfL concentrations showed no gender differences [53].”
Amyloid Beta Oligomers as Early Triggers of Neuronal Cytoskeleton Dysfunction in Alzheimer’s Disease
Gasca-Martínez, Y., Ontiveros‐Torres, M. Á., López-Gallegos, I., & Jarero-Basulto, J. J. (2026) · Pathophysiology · doi:10.3390/pathophysiology33010014 · Cited by 2
“Several studies indicate that neurofilament light chain (NFL), which plays an important role in axonal and dendritic growth [139,140], can also serve as a biomarker of neurodegeneration [141,142].”
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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