Plasma NfL Offers Better Prognostication for Neurodegeneration Than Total Tau


Data from a cohort of more than 900 individuals suggest that while total tau can add cross-sectional value in certain contexts, neurofilament light served better for prognostication of cognitive decline and imaging changes.

Michelle Mielke, PhD, professor of epidemiology and professor of neurology, Mayo Clinic

Michelle Mielke, PhD

New data from a study of plasma neurofilament light (NfL) and plasma total tau (T-tau) in individuals without dementia suggest that NfL likely serves better as a prognostic marker of both cognitive decline and changes measured via neuroimaging, though T-tau can add cross-sectional value to NfL in certain scenarios.

The data were presented at the 2021 American Academy of Neurology (AAN) Annual Meeting, April 17-22, by Jordan Marks, MD/PhD student, Mayo Clinic Alix School of Medicine. Coauthor Michelle Mielke, PhD, professor of epidemiology and professor of neurology, Mayo Clinic, noted in a press conference that to this point, the literature offering comparisons of these 2 markers has been quite limited for several cognitive and neuroimaging measures.

“Understanding which marker is associated with which aspect of neurodegeneration will inform how each marker can best be utilized for specific clinical purposes by physicians, and also what information each marker can provide,” she said. “Therefore, in the current study, we compare the association of plasma total tau and NfL as biomarkers of cognitive decline, and with neuroimaging measures of brain atrophy and white matter changes in the community-based Mayo Clinic Study of Aging.”

Overall, the study included 995 participants without dementia enrolled in the Mayo Clinic Study on Aging, all of whom had concurrent plasma NfL and T-tau data, as well as information on cognitive status and neuroimaging. Their follow-up was repeated on a 15-month basis for a median of 6.2 years, and plasma NfL and T-tau were measured on the Simoa HD-1 Platform. Mielke explained that the group also replicated the analyses in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) among 387 participants without dementia (follow up: median, 3.0 years) to ascertain the value of their findings and if it varied based on the setting and participant recruitment methodology.

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“We found that at a single point in time, plasma NfL was more strongly associated with all current measures of cognition and brain imaging variables,” she said. “However, having information on plasma T-tau levels did provide some additional information. For example, the combination of having both elevated NfL and T-tau was more strongly associated with worse memory performance at the time of assessment. Thus, T-tau may add some diagnostic benefit beyond NfL particularly for neurodegenerative diseases, such as Alzheimer disease, which have a primary memory component.”

On the neuroimaging side, the combination of an individual having both elevated NfL and T-tau at baseline was more strongly associated at cross-section with neuroimaging measures such as temporal cortex thickness and increased number of infarcts. The results also suggested that over the course of the median 6-year follow-up, NfL was more strongly associated with both cognitive and neuroimaging outcomes—findings replicated in the ADNI cohort—whereas T-tau added no prognostic value suggesting that NfL serves as a better marker of predicted outcomes, regardless of the cause of the neurodegeneration.

Mielke noted that previous studies have shown the correlations between plasma serum levels of NfL and the traditional cerebrospinal fluid (CSF) measures in the brain, with CSF levels of the biomarker implying that it is biologically representative of changes in the brain. An oft-mentioned complication or limitation of NfL, though, is that is nonspecific. “We do see it in Alzheimer disease, in vascular dementia, and it's been looked at in stroke and in multiple sclerosis, and other diseases as well. I think it is more indicative of the rate of neurodegeneration, which itself is informative,” she said.

This study was conducted with the National Institute on Aging–Alzheimer's Association criteria—sometimes referred to as the ATN (Amyloid, Tau, and Neurodegeneration) network—in mind. Mielke and colleagues sought to explore how the different markers within the “N group” or neurodegeneration, match up to cognition and neuroimaging measures. The work marks another recent foray into the assessment of blood-based biomarkers’ utility in Alzheimer disease and dementia, where the technology has experienced rapid advancement in recent years. But Mielke pointed to the similar advances being made in imaging for these diseases, which can serve as an excellent resource in diagnosis.

“MRI is absolutely essential from a neurology perspective in determining ultimate diagnoses. I think the blood-based biomarkers will be more important at the community or potentially primary care level down the road before we can get to the imaging,” she said. “[Blood-based markers] may not be perfect, but [provide] a possibility of screening those and identifying those at risk.”

For more coverage of AAN 2021, click here.

Marks J. Syrjanen J, Graff-Radford J, et al. Comparison of Neurofilament Light and Total Tau as Blood-Based Biomarkers of Neurodegeneration: Associations with Cognition and Neuroimaging Outcomes. Presented at 2021 American Academy of Neurology Annual Meeting; April 17-22. Abstract P5 219
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