Higher CSF NfL Protein Levels Linked to Risk for Mild Cognitive Impairment

cerebrospinal fluid
cerebrospinal fluid
In a population-based cohort of participants without cognitive impairment, the use of Cox proportional hazard regression models helped identify baseline CSF markers that were related to risk for mild cognitive impairment.

Elevated cerebrospinal fluid (CSF) neurofilament light (NfL) protein levels — but not CSF total tau (T-tau), phosphorylated tau (P-tau), or CSF neurogranin (Ng) levels — are a risk factor for mild cognitive impairment (MCI), according to the results of a prospective, population-based study. Findings from these analyses from the Mayo Clinic Study of Aging, conducted between January 2004 and December 2015, were published in JAMA Neurology.

The researchers sought to determine whether CSF NfL and CSF Ng levels are associated with risk for MCI, the effect size of these markers vs CSF T-tau or CSF P-tau regarding risk for MCI, and whether CSF amyloid-β 42 modified any of these associations. Cox proportional hazard regression models were used to establish whether the baseline CSF markers, continuous and in quartiles, were associated with risk for MCI among a population-based cohort of participants without cognitive impairment.

A total of 648 participants without cognitive impairment and with available CSF data and ≥1 follow-up visit were enrolled in the study. The participants were followed for a median of 3.8 (interquartile range [IQR], 2.6-5.4) years. The median age of the participants was 72.3 (IQR, 63.4 to 78.3) years. Of the enrollees, 56.5% (366 of 648) were men.

Overall, 14.8% (96 of 648) of the participants developed incident MCI. In multivariate models, the top quartile of CSF NfL, compared with the bottom quartile, was associated with a 3.1-fold increased risk for MCI (hazard ratio 3.13; 95% CI, 1.36-7.18; P =.01). Moreover, neither CSF T-tau, CSF P-tau, nor CSF Ng was associated with a risk for MCI. Furthermore, no interaction between CSF amyloid-β 42 and CSF NfL was observed with respect to risk for MCI.

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The investigators concluded that in a community population, elevated CSF NfL levels, but not CSF-tau, CSF P-tau, or CSF Ng levels, are a risk factor for MCI and are independent of brain amyloid. The data derived from this study suggest that CSF NfL may be the preferred N+ CSF biomarker in the A/T/N classification system.


Kern S, Syrjanen JA, Blennow K, et al. Association of cerebrospinal fluid neurofilament light protein with risk of mild cognitive impairment among individuals without cognitive impairment [published online November 12, 2018]. JAMA Neurol. doi: 10.1001/jamaneurol.2018.3459