Neurofilament Light Protein Strongly Predicts Cognitive Decline

November 29, 2018

Neurofilament light protein (NfL) in the cerebrospinal fluid (CSF) is a valuable biomarker of early neurodegeneration, but it is not specific for Alzheimer's pathology, a new study suggests.

Neurofilament proteins are the major scaffolding proteins of axons. On neuronal damage, they are released into the CSF and blood. They are thus being investigated as biomarkers for many different neurologic diseases.

"NfL in the CSF has previously been shown to be associated with cognitive decline but in patients who already had some cognitive impairment or at risk of developing Alzheimer's," senior author Michelle Mielke, PhD, Mayo Clinic, Rochester, Minnesota, commented to Medscape Medical News.

"We have now shown that CSF NfL is also a strong predictor of future mild cognitive impairment in cognitively unimpaired individuals in a community-based population, and this was the case in both patients with and without amyloid pathology," she said.

"What we are finding is that NfL appears to be a marker of risk for nonspecific cognitive impairment due to many different types of pathologies," Mielke added. "Our results also suggest that CSF levels of NfL are a better marker of early neurological deterioration than either tau or amyloid."

The study was published online November 12 in JAMA Neurology.

In their article, Mielke and colleagues note that previous studies have reported that elevations in levels of NfL and another protein, neurogranin (Ng), in the CSF are associated with a greater risk for progression from mild cognitive impairment to Alzheimer's dementia. Whereas NfL levels have been found to be elevated in several neurodegenerative diseases, elevations of CSF Ng levels may be specific to Alzheimer's disease.

For the current study, the researchers investigated whether elevations in CSF levels of NfL and Ng were risk factors for mild cognitive impairment. The researchers compared NfL CSF levels with CSF levels of T-tau and P-tau in a population-based cohort of participants who were without cognitive impairment at baseline.

The analyses included 648 participants (mean age, 72 years) who were without cognitive impairment. Participants had been enrolled into the prospective population-based Mayo Clinic Study of Aging between 2004 and 2015. CSF data were available for all participants, and they had all had at least one follow-up visit.

Participants were followed for a median of 3.8 years. CSF levels of NfL, Ng, amyloid (Aβ42), T-tau, and P-tau were measured. Cox proportional hazards models, with age as the timescale, were used to assess the association between levels of these proteins and risk for mild cognitive impairment after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index.

Results showed that 96 patients in the cohort (14.8%) developed incident mild cognitive impairment.

Compared with persons in the lowest quartile of CSF NfL level, those in the top quartile had a threefold increased risk for mild cognitive impairment in multivariate models (hazard ratio, 3.13; 95% confidence interval, 1.36 - 7.18).

Levels of T-tau, P-tau, or Ng in the CSF were not associated with risk for mild cognitive impairment. As expected, low CSF Aβ42 levels were associated with an increased risk for mild cognitive impairment. However, the associations between CSF NfL and risk for mild cognitive impairment were independent of CSF Aβ42.

"Collectively, these results suggest that in a community-based sample of cognitively unimpaired participants, CSF NfL is more strongly associated with risk of mild cognitive impairment compared with other CSF markers of neurodegeneration," the researchers say.

Further results showed that there was no interaction between Aβ42 and CSF NfL regarding risk for mild cognitive impairment. "Thus, CSF NfL is a risk factor for cognitive impairment for those on the Alzheimer's pathway (with low CSF Aβ42 levels) and for those who are not," the researchers state.

They point out that the lack of an association between CSF Ng level and risk for cognitive impairment in this study is consistent with results from other studies in which Ng did not predict progression from being without cognitive impairment to having mild cognitive impairment, but it did predict progression from mild cognitive impairment to Alzheimer's dementia.

These findings suggest that CSF Ng levels may be elevated later in the Alzheimer's disease process, after cognitive symptoms become apparent, the authors indicate.

Blood levels of NfL are being investigated as markers of neurodegeneration in several neurologic conditions. The most advanced studies so far have been with regard to multiple sclerosis.

"It is hoped eventually that there will be blood tests available to measure NfL as a marker of disease progression in many different neurological conditions," Mielke said. However, she does not believe measurement of NfL will be used to gauge risk for Alzheimer's or other diseases in the general population because it is too nonspecific.

"I don't think NfL will be something we measure routinely in the general population, like a cholesterol test, as levels are raised in many different neurological conditions," she added. "It is more a general marker of neurodegeneration, but I think once those other conditions have been diagnosed, NfL could be used to measure disease progression. It may also become a surrogate endpoint in clinical trials of new therapeutics."

The study was supported by funding from the National Institutes of Health (NIH)/National Institute on Aging, the GHR Foundation, and Roche Diagnostics Ltd. Dr Mielke served as a consultant to Eli Lilly and Lysosomal Therapeutics Inc and receives research support from the NIH and the US Department of Defense and unrestricted research grants from Biogen and Lundbeck.

JAMA Neurol. Published online November 12, 2018. Abstract

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