Neurofilament light (NfL) levels in blood corresponded with hallmarks of Alzheimer's disease progression, an analysis of older adults in North America found.
Longitudinal NfL levels were linked to baseline cerebrospinal fluid (CSF) biomarkers, MRI measures, PET imaging, and poor cognitive performance among Alzheimer's Disease Neuroimaging Initiative Study () participants, reported Niklas Mattsson, MD, PhD, of Lund University in Sweden, and colleagues, in .
"We could detect significant longitudinal changes in plasma NfL and these correlated with other changes related to Alzheimer's disease," Mattsson said.
Blood-based biomarkers like NfL can make it possible to detect and monitor biological changes in Alzheimer's disease with non-invasive methods, Mattsson noted. "In the future, this test may be used together with plasma measures of beta-amyloid and tau for a comprehensive work-up of Alzheimer's disease and other dementias," he told 鶹ý.
When brain neurons are damaged or dying, they release NfL protein that leaks into CSF and blood. Rising levels of NfL in CSF signal neuron loss in stroke, traumatic brain injury, Alzheimer's, multiple sclerosis, and other neurologic conditions.
Converging evidence indicates that blood-based NfL levels may be a promising biomarker of Alzheimer's neurodegeneration, observed Brian Gordon, PhD, of Washington University in St. Louis, who was not involved with the study. Among people with a rare form of familial Alzheimer's disease, for example, serum NfL predicted disease progression and brain neurodegeneration at very early stages.
The work by Mattsson and colleagues replicates other studies showing increased levels of NfL in the blood of impaired individuals, but "additionally demonstrates how longitudinal rates of change in NfL are tied to levels of cognitive impairment as well as biomarker status," Gordon told 鶹ý. "Such work is critical to understanding how NfL behaves over the course of the disease and evaluating the potential utility of NfL as a biomarker in clinical trials."
The analysis looked at 1,583 individuals from the multicenter ADNI study from September 2005 through June 2016. Of the total sample, 716 people (45%) were women, and the mean age was about 73; 401 people had no cognitive impairment (control group), 855 had mild cognitive impairment, and 327 had Alzheimer's dementia.
Baseline mean NfL levels were higher in patients with mild cognitive impairment (37.9 ng/L) and Alzheimer's dementia (45.9 ng/L) than in cognitively unimpaired controls (32.1 ng/L). Serum NfL levels increased significantly in all groups, and rates were greatest among patients with Alzheimer's dementia. A longitudinal increase in NfL corresponded with baseline variables of:
- CSF biomarkers Aβ42 (P=0.001), total tau (P=0.02), and phosphorylated tau (P=0.02)
- Small hippocampal volumes (P<0.001), thin regional cortices (P=0.009), and large ventricular volumes (P=0.002) on MRI
- Low FDG-PET uptake (P=0.01)
- Poor cognitive performance (P<0.001) on global cognitive scores
Overall, faster increases in NfL levels correlated with faster increases in CSF biomarkers of neuronal injury, faster rates of atrophy and hypometabolism, and faster worsening in global cognition.
Using the amyloid-tau-neurodegeneration in the definition of Alzheimer's disease proposed in 2018 by the National Institute on Aging and the Alzheimer's Association, Mattsson and colleagues found increased baseline NfL levels in people who were A-T+N+ (P<0.001), A+T-N+ (P<0.001), and A+T+N+ (P<0.001). Increased rates of NfL levels were seen in people who were A-T+N-(P=0.009), A-T+N+ (P=0.02), A+T-N+ (P=0.04), and A+T+N+ (P=0.002).
This analysis had several limitations, the authors noted. It did not include tau PET, which may be associated more closely with neurodegeneration than CSF tau. Amyloid beta also was assessed by CSF, not imaging. Drop-out contributed to a lack of long-term follow-up in the Alzheimer's dementia group.
The researchers also did not control for Alzheimer's subtypes and could not exclude the possibility that comorbidities, including vascular disease, may have affected the findings.
Disclosures
Data collection and sharing for this project was funded by the NIH and the Department of Defense Alzheimer's Disease Neuroimaging Initiative.
Mattsson disclosed relevant relationships with the Alzheimer's Disease Neuroimaging Initiative and Wallenberg Molecular Medicine. Co-authors disclosed relevant relationships with Roche Diagnostics, Wave, Samumed, CogRx, Brain Biomarker Solutions, Alzheon, Eli Lilly and Company, and Novartis.
Primary Source
JAMA Neurology
Mattsson N, et al "Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease" JAMA Neurology 2019; DOI:10.1001/jamaneurol.2019.0765.