Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study

Frank de Wolf, Mohsen Ghanbari, Silvan Licher, Kevin McRae-McKee, Luuk Gras, Gerrit Jan Weverling, Paulien Wermeling, Sanaz Sedaghat, M. Kamran Ikram, Reem Waziry, Wouter Koudstaal, Jaco Klap, Stefan Kostense, Albert Hofman, Roy Anderson, Jaap Goudsmit, M. Arfan Ikram

Research output: Contribution to journalArticlepeer-review

163 Scopus citations


CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-β40 and amyloid-β42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-β42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P < 0.0001] and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-β42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001], compared to the highest quartile group of amyloid-β42 and lowest of NfL. Total-tau and amyloid-β40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-β42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-β42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-β42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.

Original languageEnglish (US)
Pages (from-to)1220-1232
Number of pages13
Issue number4
StatePublished - Mar 1 2020
Externally publishedYes

Bibliographical note

Funding Information:
The dedication and commitment by which study participants, general practitioners, and pharmacists of the Ommoord district contribute to the Rotterdam Study are gratefully acknowledged. We thank all staff at the Rotterdam Study research center, facilitating assessment of participants throughout the years, and Frank J.A. van Rooij as data manager. This study was sponsored by Janssen Pharmaceutical Companies of Johnson & Johnson. Plasma concentrations of total-tau, NfL, amyloid-b40, and amyloid-b42 were assessed through the Janssen Prevention Center in Leiden, the Netherlands, on anonymized plasma samples without knowledge of disease status. Janssen had no role in study design and data collection. The Rotterdam Study is sponsored by the Erasmus Medical Centre and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. None of the funding organizations or sponsors were involved in study design, in collection, analysis, and interpretation of data, in writing of the report, or in the decision to submit the article for publication.

Publisher Copyright:
© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (


  • Ab42
  • Alzheimer's disease
  • Dementia
  • NfL
  • Plasma biomarkers
  • Humans
  • Male
  • Dementia/blood
  • tau Proteins/blood
  • Biomarkers/blood
  • Female
  • Aged
  • Early Diagnosis
  • Alzheimer Disease/blood
  • Amyloid beta-Peptides/blood
  • Cohort Studies
  • Neurofilament Proteins/blood

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article


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