Plasma neurofilament light links mortality to neuroaxonal injury beyond clinical decline and Alzheimer disease plasma biomarkers: a multi-cohort study of oldest old individuals
- 1Amsterdam UMC, Vrije Universiteit Amsterdam
Abstract
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 (A{beta}42/40, A{beta}40, A{beta}42, pTau-181, pTau-181/A{beta}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.
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BibTeX
@misc{lorenz2026plasma,
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}},
author = {L. M. C. Lorenz and S. A. M. Sikkes and M. W. Heymans and M. Hulsman and N. Tesi and M. Gouda and M. J. I. Graat and M. E. van der Hoorn and D. A. H. Daatselaar and K. Christensen and M. Thinggaard and C. E. Teunissen and H. Holstege},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.17.26365798},
url = {https://www.medrxiv.org/content/10.64898/2026.10.17.26365798v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Plasma neurofilament light links mortality to neuroaxonal injury beyond clinical decline and Alzheimer disease plasma biomarkers: a multi-cohort study of oldest old individuals
AU - L. M. C. Lorenz
AU - S. A. M. Sikkes
AU - M. W. Heymans
AU - M. Hulsman
AU - N. Tesi
AU - M. Gouda
AU - M. J. I. Graat
AU - M. E. van der Hoorn
AU - D. A. H. Daatselaar
AU - K. Christensen
AU - M. Thinggaard
AU - C. E. Teunissen
AU - H. Holstege
PY - 2026
DA - 2026/10/17
PB - medRxiv
DO - 10.64898/2026.10.17.26365798
UR - https://www.medrxiv.org/content/10.64898/2026.10.17.26365798v1
AB - 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 (A{beta}42/40, A{beta}40, A{beta}42, pTau-181, pTau-181/A{beta}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.
ER -