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Plasma neurofilament light links mortality to neuroaxonal injury beyond clinical decline and Alzheimer disease plasma biomarkers: a multi-cohort study of oldest old individuals
Lorenz LM, Sikkes SA, Heymans MW, Hulsman M, Tesi N, Gouda M, Graat MJ, van der Hoorn ME et al.. medRxiv, 2026-10-19
Topic: Plasma and spinal-fluid biomarkers
Blood-based neurofilament light (NfL) is associated with all-cause mortality, but whether this reflects neuroaxonal injury or overlaps with cognitive and functional decline remains unclear. We followed 559 individuals aged 92–107 from three oldest-old cohorts for up to 16 years: cognitively healthy Dutch centenarians and two population-based Danish cohorts. Plasma biomarkers (Aβ 42/40 , Aβ 40 , Aβ 42 , pTau-181, pTau-181/Aβ 42 , NfL, and GFAP; Dutch cohort; NfL, Danish cohorts), cognition, and activities of daily living (ADL) were evaluated against mortality. NfL was the only biomarker consistently associated with mortality (HR 1.21–1.38), whereas AD-specific biomarkers did not predict mortality despite reflecting post-mortem AD neuropathology. NfL remained associated with mortality independently of cognition and ADL; ADL mediated 13–21% across cohorts and cognition 28%, only where cognitive impairment was widespread. Mortality at extreme age is more closely linked to neuroaxonal injury than to upstream AD pathology, with NfL capturing biological vulnerability beyond cognitive and functional decline.
Key findings
- Blood-based neurofilament light (NfL) is associated with all-cause mortality, but whether this reflects neuroaxonal injury or overlaps with cognitive and functional decline remains unclear.
- NfL was the only biomarker consistently associated with mortality (HR 1.21–1.38), whereas AD-specific biomarkers did not predict mortality despite reflecting post-mortem AD neuropathology.
- NfL remained associated with mortality independently of cognition and ADL; ADL mediated 13–21% across cohorts and cognition 28%, only where cognitive impairment was widespread.
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Study details
- Participants559
- Effect sizeHR 1.21–1.38
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 37 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 23 of the 62 points we could judge it on, which is 37 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 2 / 4 | 559 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 23 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 23 of the 62 points we could judge it on is 37 out of 100. |
| Total | 37 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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APA 7th
Lorenz, L. M., Sikkes, S. A., Heymans, M. W., Hulsman, M., Tesi, N., Gouda, M., et al. (2026). Plasma neurofilament light links mortality to neuroaxonal injury beyond clinical decline and Alzheimer disease plasma biomarkers: a multi-cohort study of oldest old individuals. medRxiv. https://doi.org/10.64898/2026.10.17.26365798
Vancouver
Lorenz LM, Sikkes SA, Heymans MW, Hulsman M, Tesi N, Gouda M, et al. Plasma neurofilament light links mortality to neuroaxonal injury beyond clinical decline and Alzheimer disease plasma biomarkers: a multi-cohort study of oldest old individuals. medRxiv. 2026. doi:10.64898/2026.10.17.26365798.
BibTeX
@article{lorenz2026-7dd5e4ea,
author = {Lorenz, L. M. and Sikkes, S. A. and Heymans, M. W. and Hulsman, M. and Tesi, N. and Gouda, M. and Graat, M. J. and van der Hoorn, M. E. and others},
title = {{Plasma neurofilament light links mortality to neuroaxonal injury beyond clinical decline and Alzheimer disease plasma biomarkers: a multi-cohort study of oldest old individuals}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.10.17.26365798},
url = {https://doi.org/10.64898/2026.10.17.26365798}
}
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