Changes in blood levels of neurofilament light chain (NfL) protein over time can predict neurodegeneration years before clinical symptoms appear in familial early-onset Alzheimer’s disease (AD), new research shows.
Measuring blood NfL levels longitudinally may provide a reliable readout of the course of neurodegeneration and may represent a “powerful instrument for investigating novel Alzheimer’s therapies in clinical trials,” senior researcher Mathias Jucker, PhD, from the German Center for Neurodegenerative Diseases in Tübingen, Germany, said in a news release.
The study was published online January 21 in Nature Medicine.
NfL is a structural protein that forms the internal skeleton of neurons. When neurons are damaged, NfL is released into cerebrospinal fluid (CSF) and blood. It is being investigated as a biomarker for many different neurologic diseases.
Jucker and colleagues studied a group of families in the Dominantly Inherited Alzheimer Network who have rare genetic variants that cause early-onset AD. They focused on 243 mutation carriers and 162 family members who did not carry the risk mutations (controls).
The researchers found that NfL accumulates in blood long before the onset of clinical symptoms and that changes in blood levels predict neurodegeneration and clinical progression of presymptomatic AD.
At baseline, NfL levels in CSF and serum correlated with one another and were significantly increased in mutation carriers relative to noncarriers. In non–mutation carriers, NfL blood levels were low and largely remained steady over time.
Longitudinal, within-person analysis of serum NfL dynamics showed that NfL levels increased over time and that the annual rate of change can distinguish mutation carriers from noncarriers as early as 16 years before the estimated time of symptom onset. That’s almost a decade earlier than when using cross-sectional absolute NfL levels (16.2 years vs 6.8 years before the estimated symptom onset), the researchers note.
“It is not the absolute neurofilament concentration but its temporal evolution which is meaningful and allows predictions about the future progression of the disease,” Jucker said.
The rate of change in serum NfL was closely associated with cortical thinning seen on MRI, but less so with amyloid-β deposition, as assessed by positron-emission tomography. Serum NfL was also predictive of cognitive changes as assessed using the Mini–Mental State Examination and the Logical Memory test.
“It will be important to confirm our findings in late-onset Alzheimer’s disease and to define the time period over which neurofilament changes have to be assessed for optimal clinical predictability,” he added.
Commenting on the findings for Medscape Medical News, Heather Snyder, PhD, senior director of medical and scientific operations at the Alzheimer’s Association, described the research as important and interesting scientifically.
“This protein has been more broadly associated with neurodegeneration in general, so these results in this specific population of Alzheimer’s patients are of interest, and I’m excited to see where this work goes,” she said.
Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation in New York City, told Medscape Medical News that the findings are novel.
“What is interesting is that they didn’t just look at blood levels of this neurofilament protein but at the rate of change in the blood levels, and the really novel finding, which we haven’t seen before, is that the rate of change variable, as might be expected, is more powerful than the cross-sectional single measurement variable.”
The observations that serum NfL dynamics correlate with CSF levels, MRI findings, and results on the Mini–Mental State Exam are “validating” pieces of information, added Fillit. “A limitation is that it is in this familial genetic population, and we don’t know if the findings will be the same in the sporadic population,” he said.
The study “creates more hope that in the next 2, 3, 4, maybe 5 years, we are going to have a blood test for Alzheimer’s disease, and that’s really going to revolutionize our field the way cholesterol revolutionized heart disease,” said Fillit.
The study was supported by the Dominantly Inherited Alzheimer Network, funded by the National Institute on Aging and the German Center for Neurodegenerative Diseases; the National Institute of Neurological Diseases and Stroke Center Core for Brain Imaging; the National Science Foundation; the National Institutes of Health; the Swiss National Science Foundation; the National Institute for Health Research; the University College London Hospitals Biomedical Research Center; and the MRC Dementias Platform UK. Dr Jucker, Dr Snyder, and Dr Fillit have disclosed no relevant financial relationships.
Nat Med. Published online January 21, 2019. Abstract