Do CSF and Plasma NfL Diverge After Alzheimer’s Disease Onset?

Damaged neurons leak proteins into bodily fluids, creating potential markers for neurodegenerative diseases including Alzheimer's. But one such prospect might be less clear-cut a measure of AD progression than it once seemed. A study published November 18 in Nature Communications found that while levels of neurofilament light chain in the cerebrospinal fluid (CSF) creep up ever faster throughout the disease trajectory, in the blood this acceleration stops soon after cognitive symptoms begin. As such, the authors, led by Stephanie Schultz, Massachusetts General Hospital, Boston, and Mathias Jucker, German Center for Neurodegenerative Diseases, Tübingen, suggest that CSF NfL might be the better marker for monitoring outcomes in clinical trials.

  • Blood NfL rises decades before AD onset but its rate of increase plateaus once symptoms start.
  • CSF NfL continues to accelerate after symptom onset.
  • The CSF marker may better track neurodegeneration in symptomatic disease.

In healthy people, NfL in blood and CSF creeps up gradually with age. In autosomal-dominant AD this is noticeably faster, beginning 10 to 20 years before symptoms appear. This gap continues to grow as the NfL accumulation in carriers accelerates (Aug 2018 conference news; May 2020 news). As AD progresses, both blood and CSF NfL closely correlate with brain atrophy but not with amyloid deposition, suggesting NfL more accurately indicates neurodegeneration than do amyloid markers, such as Aβ42/40 or p-tau217.

Scientists agree that blood markers are more practical than CSF. But blood NfL has not always been a consistent measure in clinical trials. In the Trailblazer trial of donanemab in people with early cognitive decline and in the Clarity trial of lecanemab in people with mild cognitive impairment or mild dementia, there was no difference in plasma NfL between control and treatment groups (Oct 2022 news; Dec 2022 conference news). Gantenerumab, on the other hand, slowed the rise in CSF NfL (Dec 2022 conference news). Schulz, Jucker, and colleagues set out to determine whether, and in which instances, this marker was a valid measure of disease progression.

First author Anna Hofmann and colleagues analysed CSF and plasma samples from 567 people in the Dominantly Inherited Alzheimer Network Observational Study (DIAN-OBS) who were up to 20 years younger than their estimated age of symptom onset or were in early stages of the disease. The researchers compiled samples taken every one to two years from the same individuals to get a picture of what happens over the course of ADAD. Hofmann found that in the CSF of ADAD mutation carriers, the uptick in NfL continued to accelerate after symptoms began. But in their plasma, the accumulation rate plateaued (image below).

Tapering. Spaghetti plots show that CSF NFL (right) rises more quickly in people with ADAD mutations (red) than in noncarriers (gray) and that this accelerates as disease progresses. In plasma (left), the NfL rise in carriers plateaus soon after symptom onset. [Courtesy of Hofmann, et al., 2024.]

The data also indicate that the correlation between CSF and blood NfL shifts over time. “That the relationship between the central nervous system and peripheral biomarkers changes across the disease is quite important, given people are moving to implement more blood-based biomarkers,” Schultz said. She thinks that while blood NfL may be useful for studying presymptomatic Alzheimer's, tracking CSF levels would be more accurate for middle or later stages.

It's not entirely clear why NfL would have different trajectories in different bodily fluids, although Schultz said this is also true of other biomarkers, such as p-tau217 (Therriault et al., 2023). Hypotheses include blood-brain barrier breakdown during disease progression, age- or disease-related changes in how the body clears proteins from blood or CSF, or immune responses that change over time.

Philip Weston, University College London, who was not involved in the study, was surprised by the difference between plasma and CSF NfL trajectories. “While a similar pattern has been seen in Huntington’s disease, the mechanism remains poorly understood, and more work is needed to learn why it happens,” he said (Rodrigues, et al., 2020). 

This study confirmed previous ones, finding that NfL levels don’t closely correlate with amyloid deposition. This aligns with research from Jucker’s group. It found that, in mice at least, the brain seems to reach a “tipping point,” whereby once amyloid levels reach half their maximum load, neurodegeneration—and NfL release—progresses independently of amyloid (Aug 2022 conference news; Rother et al., 2022). 

Does this divergence between CSF and plasma NfL hold up in late-onset AD? This study didn’t address this question, but one analysis of ADNI data suggests not. Among 1,583 people in this longitudinal study of LOAD, whose had average age was 73, blood NfL started rising slowly years before symptoms and rose faster, rather than plateauing, once people developed full-blown Alzheimer's dementia (May 2019 news).

Schultz wondered whether other factors could explain the acceleration in this cohort, who are older than most people in DIAN. She said it can be difficult to reliably distinguish patterns amid the “noise of age,” since kidney function, body-mass index, and other factors that change during normal aging can all affect NfL levels in the blood independently of neurodegeneration (Vermunt, et al., 2022).

The ADNI analysis didn’t compare blood and CSF NfL directly. Schultz said her next step will be to do that in sporadic AD.—Sara Reardon

Sara Reardon is a freelance writer in Bozeman, Montana.

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References

News Citations

  1. Blood Test for Neurofilament Light Chain Kicks Up Biomarker Research
  2. In Colombian Alzheimer’s Kindred, Blood NfL Climbs 22 Years Before Symptoms
  3. In TRAILBLAZER, Plasma GFAP Falls, but NfL Continues to Rise
  4. Dare We Say Consensus Achieved: Lecanemab Slows the Disease
  5. Gantenerumab Mystery: How Did It Lose Potency in Phase 3?
  6. Can BACE Inhibitors Stage a Comeback?
  7. Plasma NfL Goes the Distance in Alzheimer’s

Paper Citations

  1. Therriault J, Servaes S, Tissot C, Rahmouni N, Ashton NJ, Benedet AL, Karikari TK, Macedo AC, Lussier FZ, Stevenson J, Wang YT, Fernandez-Arias J, Stevenson A, Socualaya KQ, Haeger A, Nazneen T, Aumont É, Hosseini A, Rej S, Vitali P, Triana-Baltzer G, Kolb HC, Soucy JP, Pascoal TA, Gauthier S, Zetterberg H, Blennow K, Rosa-Neto P. Equivalence of plasma p-tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease. Alzheimers Dement. 2023 Apr 20; PubMed.
  2. Rodrigues FB, Byrne LM, Tortelli R, Johnson EB, Wijeratne PA, Arridge M, De Vita E, Ghazaleh N, Houghton R, Furby H, Alexander DC, Tabrizi SJ, Schobel S, Scahill RI, Heslegrave A, Zetterberg H, Wild EJ. Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease. Sci Transl Med. 2020 Dec 16;12(574) PubMed.
  3. Rother C, Uhlmann RE, Müller SA, Schelle J, Skodras A, Obermüller U, Häsler LM, Lambert M, Baumann F, Xu Y, Bergmann C, Salvadori G, Loos M, Brzak I, Shimshek D, Neumann U, Dominantly Inherited Alzheimer Network, Walker LC, Schultz SA, Chhatwal JP, Kaeser SA, Lichtenthaler SF, Staufenbiel M, Jucker M. Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae. Nat Commun. 2022 Nov 28;13(1):7333. PubMed.
  4. Vermunt L, Otte M, Verberk IM, Killestein J, Lemstra AW, van der Flier WM, Pijnenburg YA, Vijverberg EG, Bouwman FH, Gravesteijn G, van de Berg WD, Scheltens P, van Harten AC, Willemse EA, Teunissen CE. Age- and disease-specific reference values for neurofilament light presented in an online interactive support interface. Ann Clin Transl Neurol. 2022 Nov;9(11):1832-1837. Epub 2022 Oct 5 PubMed.

Further Reading

Primary Papers

  1. Hofmann A, Häsler LM, Lambert M, Kaeser SA, Gräber-Sultan S, Obermüller U, Kuder-Buletta E, la Fougere C, Laske C, Vöglein J, Levin J, Fox NC, Ryan NS, Zetterberg H, Llibre-Guerra JJ, Perrin RJ, Ibanez L, Schofield PR, Brooks WS, Day GS, Farlow MR, Allegri RF, Chrem Mendez P, Ikeuchi T, Kasuga K, Lee JH, Roh JH, Mori H, Lopera F, Bateman RJ, McDade E, Gordon BA, Chhatwal JP, Jucker M, Schultz SA, Dominantly Inherited Alzheimer Network. Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer's disease. Nat Commun. 2024 Nov 18;15(1):9982. PubMed.

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