[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Mattsson  N, Carrillo  MC, Dean  RA,  et al.  Revolutionizing Alzheimer’s disease and clinical trials through biomarkers.  Alzheimers Dement (Amst). 2015;1(4):412-419.PubMedGoogle Scholar
Blennow  K, Hampel  H, Weiner  M, Zetterberg  H.  Cerebrospinal fluid and plasma biomarkers in Alzheimer disease.  Nat Rev Neurol. 2010;6(3):131-144.PubMedGoogle ScholarCrossref
Frisoni  GB, Fox  NC, Jack  CR  Jr, Scheltens  P, Thompson  PM.  The clinical use of structural MRI in Alzheimer disease.  Nat Rev Neurol. 2010;6(2):67-77.PubMedGoogle ScholarCrossref
Nordberg  A, Rinne  JO, Kadir  A, Långström  B.  The use of PET in Alzheimer disease.  Nat Rev Neurol. 2010;6(2):78-87.PubMedGoogle ScholarCrossref
Blennow  K, Mattsson  N, Schöll  M, Hansson  O, Zetterberg  H.  Amyloid biomarkers in Alzheimer’s disease.  Trends Pharmacol Sci. 2015;36(5):297-309.PubMedGoogle ScholarCrossref
Zetterberg  H.  Neurofilament light: a dynamic cross-disease fluid biomarker for neurodegeneration.  Neuron. 2016;91(1):1-3.PubMedGoogle ScholarCrossref
Zetterberg  H, Skillbäck  T, Mattsson  N,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression.  JAMA Neurol. 2016;73(1):60-67.PubMedGoogle ScholarCrossref
Gaiottino  J, Norgren  N, Dobson  R,  et al.  Increased neurofilament light chain blood levels in neurodegenerative neurological diseases.  PLoS One. 2013;8(9):e75091.PubMedGoogle ScholarCrossref
Bacioglu  M, Maia  LF, Preische  O,  et al.  Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases.  Neuron. 2016;91(1):56-66.PubMedGoogle ScholarCrossref
Kuhle  J, Barro  C, Andreasson  U,  et al.  Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa.  Clin Chem Lab Med. 2016;54(10):1655-1661.PubMedGoogle ScholarCrossref
Gisslén  M, Price  RW, Andreasson  U,  et al.  Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study.  EBioMedicine. 2015;3:135-140.PubMedGoogle ScholarCrossref
Rojas  JC, Karydas  A, Bang  J,  et al.  Plasma neurofilament light chain predicts progression in progressive supranuclear palsy.  Ann Clin Transl Neurol. 2016;3(3):216-225.PubMedGoogle ScholarCrossref
Petersen  RC, Aisen  PS, Beckett  LA,  et al.  Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization.  Neurology. 2010;74(3):201-209.PubMedGoogle ScholarCrossref
McKhann  G, Drachman  D, Folstein  M, Katzman  R, Price  D, Stadlan  EM.  Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease.  Neurology. 1984;34(7):939-944.PubMedGoogle ScholarCrossref
Rohrer  JD, Woollacott  IOC, Dick  KM,  et al.  Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia.  Neurology. 2016;87(13):1329-1336.PubMedGoogle ScholarCrossref
Shaw  LM, Vanderstichele  H, Knapik-Czajka  M,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Cerebrospinal fluid biomarker signature in Alzheimer’s Disease Neuroimaging Initiative subjects.  Ann Neurol. 2009;65(4):403-413.PubMedGoogle ScholarCrossref
Jack  CR  Jr, Bernstein  MA, Fox  NC,  et al.  The Alzheimer’s Disease Neuroimaging Initiative (ADNI): MRI methods.  J Magn Reson Imaging. 2008;27(4):685-691.PubMedGoogle ScholarCrossref
Jack  CR  Jr, Wiste  HJ, Weigand  SD,  et al.  Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings.  Brain. 2015;138(pt 12):3747-3759.PubMedGoogle ScholarCrossref
Schwarz  C, Fletcher  E, DeCarli  C, Carmichael  O. Fully-automated white matter hyperintensity detection with anatomical prior knowledge and without FLAIR. Inf Process Med Imaging. 2009;21:239-251. PubMed
Landau  SM, Mintun  MA, Joshi  AD,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Amyloid deposition, hypometabolism, and longitudinal cognitive decline.  Ann Neurol. 2012;72(4):578-586.PubMedGoogle ScholarCrossref
Bergman  J, Dring  A, Zetterberg  H,  et al.  Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS.  Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e271.PubMedGoogle ScholarCrossref
Mattsson  N, Zetterberg  H, Janelidze  S,  et al; ADNI Investigators.  Plasma tau in Alzheimer disease.  Neurology. 2016;87(17):1827-1835.PubMedGoogle ScholarCrossref
Buchhave  P, Minthon  L, Zetterberg  H, Wallin  AK, Blennow  K, Hansson  O.  Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia.  Arch Gen Psychiatry. 2012;69(1):98-106.PubMedGoogle ScholarCrossref
Jack  CR  Jr, Knopman  DS, Jagust  WJ,  et al.  Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade.  Lancet Neurol. 2010;9(1):119-128.PubMedGoogle ScholarCrossref
Vos  SJ, Xiong  C, Visser  PJ,  et al.  Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study.  Lancet Neurol. 2013;12(10):957-965.PubMedGoogle ScholarCrossref
Mattsson  N.  CSF biomarkers in neurodegenerative diseases.  Clin Chem Lab Med. 2011;49(3):345-352.PubMedGoogle ScholarCrossref
Mattsson  N, Insel  PS, Palmqvist  S,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Cerebrospinal fluid tau, neurogranin, and neurofilament light in Alzheimer’s disease.  EMBO Mol Med. 2016;8(10):1184-1196.PubMedGoogle ScholarCrossref
Original Investigation
March 27, 2017

Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease

Author Affiliations
  • 1Clinical Memory Research Unit, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden
  • 2Memory Clinic, Skåne University Hospital, Scania, Sweden
  • 3Department of Neurology, Skåne University Hospital, Scania, Sweden
  • 4Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • 5Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Möndal, Sweden
  • 6Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, England
JAMA Neurol. 2017;74(5):557-566. doi:10.1001/jamaneurol.2016.6117
Key Points

Question  What is the importance of plasma neurofilament light in Alzheimer disease?

Findings  In this case-control study of 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with Alzheimer disease dementia, plasma neurofilament light was associated with Alzheimer disease and correlated with future progression of cognitive decline, brain atrophy, and brain hypometabolism.

Meaning  Plasma neurofilament light may be a promising noninvasive biomarker for Alzheimer disease.


Importance  Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias.

Objective  To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration.

Design, Setting, and Participants  In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer’s Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016.

Main Outcomes and Measures  Associations were tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism.

Results  Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ρ = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally).

Conclusions and Relevance  Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.