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Original Investigation
November 12, 2018

Association of Cerebrospinal Fluid Neurofilament Light Protein With Risk of Mild Cognitive Impairment Among Individuals Without Cognitive Impairment

Author Affiliations
  • 1Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 2Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  • 3University of Gothenburg, Mölndal, Sweden
  • 4Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • 5Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Institute of Neurology, University College London, Queen Square, London, England
  • 6United Kingdom Dementia Research Institute at University College London, London, England
  • 7Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 8Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands
  • 9Department of Radiology, Mayo Clinic, Rochester, Minnesota
JAMA Neurol. Published online November 12, 2018. doi:10.1001/jamaneurol.2018.3459
Key Points

Question  Are cerebrospinal fluid (CSF) neurofilament light protein (NfL) and neurogranin (Ng) levels associated with the risk of incident mild cognitive impairment (MCI), and how do these markers compare with CSF total (T-tau) or phosphorylated tau (P-tau) for risk of MCI in the general community?

Findings  In this population-based study, compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3-fold increased risk of MCI. Neither CSF T-tau, P-tau, nor Ng levels were associated with risk of MCI.

Meaning  Elevated CSF NfL levels, but not T-tau, P-tau, or Ng levels, are associated with risk of MCI in a community population.

Abstract

Importance  Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau).

Objective  To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-β (Aβ42) modified these associations.

Design, Setting and Participants  The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6-5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Aβ42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Aβ42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Aβ42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid.

Main Outcomes and Measures  Risk of MCI.

Results  At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5%) were men; 96 (14.8%) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95% CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Aβ42 and CSF NfL for risk of MCI.

Conclusions and Relevance  Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid.

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