In carriers of a pathogenic mutation in presenilin 1, plasma levels of the neurodegeneration marker neurofilament light (NfL) start to diverge from those in noncarriers more than two decades prior to when Alzheimer’s symptoms begin. That was the upshot of a study published May 26 in the Lancet Neurology. Led by Kaj Blennow at the University of Gothenberg in Sweden and Francisco Lopera of Universidad de Antioquia in Medellin, Colombia, the study leveraged both longitudinal and cross-sectional data on blood samples that more than 2,000 members of the Colombian kindred harboring the PSEN1-E280A mutation had donated to help scientists chart the rise of biomarkers of AD.
- Massive study measured plasma NfL in Colombian familial AD kindred.
- As a group, carriers diverged from noncarriers 22 years before estimated symptom onset.
- In individuals, the marker distinguished carriers and noncarriers three years before onset.
“In general, this and other data in studies of neurodegenerative diseases suggest that serum/plasma NfL is a marker of neurodegeneration that will be useful in prognosis as well as in assessing response to disease-modifying therapies,” wrote David Holtzman of Washington University in St. Louis in a comment to Alzforum.
Alzforum covered the findings when Eric Reiman of Banner Alzheimer’s Institute in Phoenix presented them at AAIC last year (Aug 2019 conference news).
The study included 1,070 mutation carriers and 1,074 age-matched noncarriers with baseline data, as well as 242 carriers and 262 noncarriers with serial measurements. Participants ranged from 8 to 75 years of age. Gothenberg scientists Blennow and Henrik Zetterberg used an ultrasensitive Simoa assay to measure plasma NfL.
Using the cross-sectional data, co-first authors Yakeel Quiroz of Massachusetts General Hospital in Boston, Zetterberg, and Reiman found that while plasma NfL crept up with age in both carriers and noncarriers, the average NfL concentration of carriers split from noncarriers at age 22, which also happens to be 22 years prior to estimated symptom onset. Groups overlapped significantly, especially at younger ages. Not until three years prior to symptom onset were the differences in plasma NfL large enough to sensitively distinguish individual carriers from noncarriers.
In a subset of 504 participants who were followed longitudinally for an average of six years, baseline plasma NfL correlated with its subsequent rise in carriers. Baseline NfL also predicted subsequent slippage on the MMSE in both carriers and noncarriers, and in memory scores in carriers.
The findings mesh with those recently reported from the Dominantly Inherited Alzheimer’s Network, in which plasma NfL diverged in mutation carriers starting 16 years prior to symptom onset (Jan 2019 news). Holtzman chalked up the earlier detection of rising plasma NfL in the Colombian cohort to its larger size, and to the fact that its members all carry the same mutation. The DIAN cohort comprises more than 250 different pathogenic mutations in APP, presenilin 1, and presenilin 2.
Mathias Jucker of the German Center for Neurodegenerative Diseases, Tübingen, was pleased to see convergence between two separate autosomal-dominant AD data sets. “It is my understanding that these data also match with the more difficult-to-do studies in sporadic AD. It confirms that NfL is an important readout when we aim at presymptomatic treatment,” Jucker wrote to Alzforum.
Leslie Shaw of the University of Pennsylvania in Philadelphia noted that NfL is a general marker of degenerating neurons, whose plasma concentration can rise due to all sorts of non-AD pathologies or other neuronal insults. Still, it may serve as a useful gauge of disease stage when combined with specific markers of amyloid and tau pathology. “Future studies are ongoing and needed to define how well plasma NfL reflects neurodegeneration and adds value in prediction of disease state and cognitive decline in the individual patient,” Shaw wrote. —Jessica Shugart
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- Quiroz YT, Zetterberg H, Reiman EM, Chen Y, Su Y, Fox-Fuller JT, Garcia G, Villegas A, Sepulveda-Falla D, Villada M, Arboleda-Velasquez JF, Guzmán-Vélez E, Vila-Castelar C, Gordon BA, Schultz SA, Protas HD, Ghisays V, Giraldo M, Tirado V, Baena A, Munoz C, Rios-Romenets S, Tariot PN, Blennow K, Lopera F. Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study. Lancet Neurol. 2020 Jun;19(6):513-521. Epub 2020 May 26 PubMed.