Neurofilament could shed light on why trials fail - or succeed
LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.
At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.
While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.
Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).
Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.
“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”
A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).
In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”
Dr. Eric Reiman
Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”
Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.
“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.
Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”
Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”
Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.