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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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Fischl, B., Salat, D. H., Busa, E., Albert, M., Dieterich, M., Haselgrove, C., van der Kouwe, A., Killiany, R., Kennedy, D., Klaveness, S., et al. (2002) · Neuron · doi:10.1016/s0896-6273(02)00569-x · Cited by 8,610
The Alzheimer’s disease neuroimaging initiative (ADNI): MRI methods
Jack, C. R., Bernstein, M. A., Fox, N. C., Thompson, P., Alexander, G., Harvey, D., Borowski, B., Britson, P. J., L. Whitwell, J., Ward, C., et al. (2008) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.21049 · Cited by 4,347
Self-citationAutomatically Parcellating the Human Cerebral Cortex
Fischl, B. R. (2003) · Cerebral Cortex · doi:10.1093/cercor/bhg087 · Cited by 4,208
Blennow, K., de Leon, M. J., & Zetterberg, H. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69113-7 · Cited by 3,134
Self-citationCerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects
Shaw, L. M., Vanderstichele, H., Knapik‐Czajka, M., Clark, C. M., Aisen, P. S., Petersen, R. C., Blennow, K., Soares, H., Simon, A., Lewczuk, P., et al. (2009) · Annals of Neurology · doi:10.1002/ana.21610 · Cited by 2,065
Self-citationHua, K., Zhang, J., Wakana, S., Jiang, H., Li, X., Reich, D. S., Calabresi, P. A., Pekar, J. J., van Zijl, P. C. M., & Mori, S. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2007.07.053 · Cited by 1,507
A white matter disorder in dementia of the Alzheimer type: A pathoanatomical study
Brun, A., & Englund, E. (1986) · Annals of Neurology · doi:10.1002/ana.410190306 · Cited by 1,014
Alzheimer' Disease as a Disconnection Syndrome?
Delbeuck, X., der Linden, M. V., & Collette, F. (2003) · Neuropsychology Review · doi:10.1023/a:1023832305702 · Cited by 705
White matter changes in mild cognitive impairment and AD: a diffusion tensor imaging study
Medina, D., deToledo-Morrell, L., Urresta, F., Gabrieli, J. D. E., Moseley, M., Fleischman, D., Bennett, D. A., Leurgans, S., Turner, D. A., & Stebbins, G. T. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.03.026 · Cited by 492
Rose, S. (2000) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.69.4.528 · Cited by 465
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NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.02.018 · Cited by 10,537
“neurogranin is presumed to measure synaptic degeneration and loss [170,171], and neurofilament light chain [172] is presumed to measure axonal injury.”
Self-citationNeurofilaments as biomarkers in neurological disorders
Khalil, M., Teunissen, C. E., Otto, M., Piehl, F., Sormani, M. P., Gattringer, T., Barro, C., Kappos, L., Comabella, M., Fazekas, F., et al. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0058-z · Cited by 1,988
Self-citationZhou, Y., Song, W. M., Andhey, P. S., Swain, A., Levy, T., Miller, K. R., Poliani, P. L., Cominelli, M., Grover, S., Gilfillan, S., et al. (2020) · Nature Medicine · doi:10.1038/s41591-019-0695-9 · Cited by 1,150
Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease
Mattsson, N., Andreasson, U., Zetterberg, H., Blennow, K., & Initiative, F. T. A. D. N. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2016.6117 · Cited by 1,070
“This exclusion may have made it difficult to detect subtle associations between plasmaNFLandwhitematter pathologic findings andmayexplain the surprising finding that plasmaNFLdid not correlate with WMHs, despite that CSF NFL has been considered a markerofwhitematterpathologic features,(26) including inAD.(7) Future st…”
InfluentialSelf-citationBlood-based biomarkers for Alzheimer's disease: towards clinical implementation
Teunissen, C. E., Verberk, I. M. W., Thijssen, E. H., Vermunt, L., Hansson, O., Zetterberg, H., van der Flier, W. M., Mielke, M. M., & del Campo, M. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00361-6 · Cited by 1,045
“67,68 Concentrations of NfL increase with age, which complicates interpretation of results.”
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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