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Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression
Zetterberg H, Skillbäck T, Mattsson N, Trojanowski JQ, Portelius E, Shaw LM, Weiner MW, Blennow K et al.. JAMA neurology, 2016-01-01
Topic: Amyloid, tau and blood-test diagnosis
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 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.
Key findings
- Objective To test whether CSF NFL concentration is associated with cognitive decline and imaging evidence of neurodegeneration and white matter change in AD.
- 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).
Why it matters
In 397 people from the Alzheimer's Disease Neuroimaging Initiative (95 with Alzheimer's dementia, 192 with mild cognitive impairment, 110 cognitively normal), levels of neurofilament light, a general marker of damage to nerve fibres, in spinal fluid were higher in every patient group than in controls (median 1479 pg/mL in Alzheimer's dementia, 1336 in MCI that progressed, 1182 in MCI that did not, versus 1047). The study also tested whether these levels tracked later cognitive decline, brain shrinkage and white-matter change. The values overlap a lot between groups, and the marker is not specific to Alzheimer's, so this says nothing about diagnosing an individual, treatment or prevention.
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Study details
- Study designlongitudinal study
- Participants95
- Evidence strengthModerate
How this study scored 67/100
Published in a leading specialty journal, and it is a longitudinal study following the same people over time. Scored zero for effect reported and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 64 of the 96 points we could judge it on, which is 67 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (JAMA neurology) |
| Journal's citation record | 2 / 4 | JAMA Neurology: journal h-index 235 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2016 — within 20 year(s) of the newest study here |
| Sample size | 1 / 4 | 95 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 486 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 40.5 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 5 / 6 | Cited 23.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 34 other studies in this library |
| Still being cited | 3 / 4 | Cited 117 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26524180) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 64 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 64 of the 96 points we could judge it on is 67 out of 100. |
| Total | 67 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1001/jamaneurol.2015.3037
- PubMed: 26524180
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Zetterberg, H., Skillbäck, T., Mattsson, N., Trojanowski, J. Q., Portelius, E., Shaw, L. M., et al. (2016). Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression. JAMA neurology. https://doi.org/10.1001/jamaneurol.2015.3037
Vancouver
Zetterberg H, Skillbäck T, Mattsson N, Trojanowski JQ, Portelius E, Shaw LM, et al. Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression. JAMA neurology. 2016. doi:10.1001/jamaneurol.2015.3037. PMID: 26524180.
BibTeX
@article{zetterberg2016-26524180,
author = {Zetterberg, H. and Skillbäck, T. and Mattsson, N. and Trojanowski, J. Q. and Portelius, E. and Shaw, L. M. and Weiner, M. W. and Blennow, K. and others},
title = {{Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression}},
journal = {JAMA neurology},
year = {2016},
doi = {10.1001/jamaneurol.2015.3037},
pmid = {26524180},
url = {https://doi.org/10.1001/jamaneurol.2015.3037}
}
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