At the Alzheimer’s Association International Conference, held July 14–18 in Los Angeles, a blood test indicating that neurons in the brain are degenerating generated considerable buzz. Eric Reiman, Banner Alzheimer’s Institute, Phoenix, presented data on plasma neurofilament light (NfL) that had been measured in 2,144 Colombian people aged 8–75. They all came from families plagued with a presenilin 1 mutation, whose carriers develop dementia in their 40s. The plasma NfL measure distinguished mutation carriers from noncarriers as early as age 22, which also happens to be 22 years before their expected age of symptom onset. Plasma NfL rose fastest just before symptoms began, and a rapid rise predicted declining cognition and brain shrinkage.
The data come on the heels of two smaller studies in autosomal-dominant AD (Jan 2019 news; Nov 2017 news), and the first longitudinal study showing that plasma NfL tracks disease progression in late-onset AD, as well (May 2019 news).
The Colombian cohort comprises 25 extended families who inherited the PSEN1 E280A, aka Paisa, mutation. The Colombian neurologist Francisco Lopera, Universidad de Antioquia, Medellin, together with Ken Kosik, University of California Santa Barbara, and others described the families 22 years ago (Lopera et al., 1997). Since then, scientists have learned that the brains of mutation carriers are subtly different starting in childhood, and their cognition starts to slide subtly in the late 30s, although there is some variability in age of onset. Mild cognitive impairment develops at 44 and dementia at 49 (Fuller et al., 2019).
In a study, a large collaboration of researchers measured plasma NfL in 2,144 mutation carriers and noncarriers drawn from the Alzheimer Prevention Initiative research registry in Medellin. This registry has become an extraordinary resource, having enrolled 5,846 people from Colombian families affected by the E280A mutation, including 1,192 carriers, 1,119 of whom are living, and six homozygotes (Kosik et al., 2015). The API researchers have blood and DNA samples for all, and clinical assessments for many. Some blood donors underwent brain scans, and donated CSF for biomarker analysis. For 504 participants, the scientists had multiple blood samples spanning an average of five years, and 399 of those had longitudinal clinical data as well.
Yakeel Quiroz, Massachusetts General Hospital, Boston, coordinated the study, selecting 1,070 carriers and 1,074 age- and sex-matched noncarriers whose plasma went to the lab of Kaj Blennow and Henrik Zetterberg at the University of Gothenberg, Sweden, and was analyzed using their ultra-sensitive single molecule array (SIMOA) NfL assay. Both carriers and noncarriers averaged 30 years old, but included children as young as 8 and people in their 70s. The average plasma NfL in the mutation carriers was 18 pg/ml, versus 9 pg/ml for noncarriers. Despite large variation in both groups, the difference was statistically significant.
As expected, in the cross-sectional analysis NfL levels were higher in older people, but much more so in carriers. A linear regression analysis showed the curves diverged at age 22, or 22 years before the median age of MCI onset at 44. The investigators got the same result when they calculated the rate of change of NfL in the 504 mutation carriers and noncarriers for whom they had longitudinal data. NfL accumulation ramped up in carriers 22 years before the median age of MCI onset.
That is even earlier than in a previous study of 408 people in the DIAN cohort, which picked up an accelerated rise in NfL16 years before symptom onset (Priesche et al., 2019). Reiman said the API team analyzed the Colombian data exactly as the DIAN researchers had done and, indeed, received help from Brian Gordon and Stephanie Schultz at Washington University, St. Louis. The differences may be due to the larger sample size and the fact that all the Colombian carriers have the same mutation, as opposed to the more than 40 different mutations across three genes represented in DIAN.
Plasma NfL foretold a person’s clinical course, too. In 38 cognitively impaired and 119 as-yet-unimpaired carriers who were followed clinically for about five years, the former had more than three times higher absolute NfL levels and 13 times the annual rate of change of the latter, who were themselves slightly higher than noncarriers. However, Reiman cautioned that the results need adjustment for age and sex. At 50 on average, the impaired carriers were older than the unimpaired carriers or noncarriers, who averaged 32 and 27 years old, respectively.
Likewise, in a cross-sectional analysis, higher baseline plasma NfL correlated with lower MMSE and word-list-recall scores among both impaired and unimpaired carriers. Longitudinally, both baseline plasma NfL and annual rate of change correlated with annual clinical decline rates. Again, neither is adjusted for age yet.
In response to audience questions, Reiman said the relationship between plasma NfL and amyloid status, ApoE4, and other factors in this group still needs to be examined. Previous work suggests that E280A carriers who have an Apoe4 allele suffer earlier clinical onset. “We now have the opportunity to use biomarkers such as NfL as endophenotypes to see if pathological changes are accelerated by ApoE4. These are exactly the kinds of studies one could leverage in this cohort,” he said.
Others in the audience asked how the rate of NfL accumulation changes over time. Reiman noted a dramatic increase in plasma NfL a few years before disease onset, and suggested that this may be the best time to detect changes in response to treatment. “We’ll have a better chance of seeing a reduction of high levels rather than slowing of a gradual increase. At age 22, we don’t have much power to see a change over time, so we’ll be doing studies in the late preclinical/early clinical stage.”
This NfL analysis represents the first biomarker study on this large collection of plasma samples. Next, API researchers will measure phospho-tau 181 in them.
These results are raising hope that NfL will provide a relatively cheap, quick, and easy readout to inform a person’s prognosis. Importantly, NfL could signal that a trial participant is responding to treatments aimed at slowing neurodegeneration. When axons degenerate, the NfL protein gets shed into the CSF, from which it makes its way into blood.
Separately at AAIC, Charlotte Teunissen, who leads a fluid biomarker lab at at Vrije University Medical Center, Amsterdam, presented ongoing work on a multicenter validation study on blood NfL assays. This kind of applied science is necessary to create reliable, certified assays that are suitable for routine clinical use.—Pat McCaffrey
- Neurofilament in Blood Foretells Early Onset Alzheimer’s
- Serum NfL Detects Preclinical AD, Reflects Clinical Benefit
- Plasma NfL Goes the Distance in Alzheimer’s
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- Fuller JT, Cronin-Golomb A, Gatchel JR, Norton DJ, Guzmán-Vélez E, Jacobs HI, Hanseeuw B, Pardilla-Delgado E, Artola A, Baena A, Bocanegra Y, Kosik KS, Chen K, Tariot PN, Johnson K, Sperling RA, Reiman EM, Lopera F, Quiroz YT. Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer's Disease: A Comprehensive Review of the Colombian Kindred. J Prev Alzheimers Dis. 2019;6(2):112-120. PubMed.
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- Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, Gräber S, Kuder-Buletta E, LaFougere C, Laske C, Vöglein J, Levin J, Masters CL, Martins R, Schofield PR, Rossor MN, Graff-Radford NR, Salloway S, Ghetti B, Ringman JM, Noble JM, Chhatwal J, Goate AM, Benzinger TL, Morris JC, Bateman RJ, Wang G, Fagan AM, McDade EM, Gordon BA, Jucker M, Dominantly Inherited Alzheimer Network. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med. 2019 Feb;25(2):277-283. Epub 2019 Jan 21 PubMed.
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