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Clinical Trial
. 2025 Aug;21(8):e70554.
doi: 10.1002/alz.70554.

Arterial stiffness moderates the link between NfL and cognition: The IGNITE study

Amani M Norling  1   2 , Lewis A Lipsitz  1   2 , Alyssa B Dufour  1   2 , Thomas G Travison  1   2 , Kelsey R Sewell  3   4 , Audrey M Collins  3 , Lu Wan  3 , George Grove  5 , Haiqing Huang  3 , Lauren E Oberlin  3   6 , Shivangi Jain  3 , Thomas K Karikari  7 , Jill K Morris  8   9 , John M Jakicic  10 , Edward McAuley  11   12 , Arthur F Kramer  11   13   14 , Charles H Hillman  13   14   15 , Eric D Vidoni  8   9 , Sandra A Billinger  8   9 , Jeffrey M Burns  8   9 , Anna L Marsland  5 , Chaeryon Kang  7 , Kirk I Erickson  3
Affiliations
Clinical Trial

Arterial stiffness moderates the link between NfL and cognition: The IGNITE study

Amani M Norling et al. Alzheimers Dement. 2025 Aug.

Abstract

Introduction: Arterial stiffness (carotid-femoral pulse wave velocity [cfPWV]) and plasma neurofilament light (NfL), markers of vascular and neuroaxonal aging, are linked to cognitive decline. Whether higher cfPWV amplifies the NfL-cognition relationship remains unclear.

Methods: Cognitively unimpaired older adults (N = 570) were assessed using composite cognitive scores from confirmatory factor analysis. cfPWV was dichotomized at the median. Plasma NfL was quantified on a Single Moleculte Array-High Definition, model X (SIMOA-HD X).

Results: Higher NfL correlated with poorer performance across all cognitive domains (p < 0.05), and higher cfPWV was linked to worse episodic memory, working memory, and processing speed (p < 0.05). NfL× cfPWV interactions were significant for episodic (β = 0.289, p = 0.048) and working memory (β = 0.287, p = 0.025), with stronger NfL-cognition associations in the higher cfPWV group (episodic memory: β = -0.324, p < 0.01; working memory: β = -0.343, p < 0.01).

Discussion: Greater cfPWV amplified the association between NfL-related axonal degeneration and cognitive decline.

Trial registration: ClinicalTrials.gov: NCT02875301 HIGHLIGHTS: Neurofilament light (NfL) and carotid-femoral pulse wave velocity (cfPWV) each correlate with poorer cognitive function in older adults. Higher cfPWV exacerbates the link between NfL and cognitive deficits. Arterial stiffness may worsen NfL-related cognitive decline. Findings reveal synergy between vascular and neurodegenerative aging markers. Examining NfL or cfPWV alone may miss their synergistic effects on cognition.

Keywords: cardiorespiratory fitness; cognitive aging; episodic memory; neurofilament light; older adults; pulse wave velocity; vascular health; working memory.

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Conflict of interest statement

None for A.M.N., L.A.L., A.B.D., T.G.T., K.R.S., A.M.C., L.W., G.G., H.H., L.E.O., S.J., J.K.M., J.M.J., E.C., A.F.K., C.H.H., E.D.V., S.A.B., J.M.B., A.L.M., and C.K. T.K.K. has consulted/served on advisory board for Quanterix Corporation, SpearBio Inc., and Neurogen Biomarking LLC.; has stock equity interest in Neurogen Biomarking LLC.; and has received research support from Janssen Research Laboratories, outside the submitted work. He has received honoraria for speaker/grant review engagements from the National Institutes of Health (NIH), University of Pennsylvania (UPENN), University of Wisconsin‐Madison, AdventHealth, Brain Health conference, Barcelona‐Pittsburgh conference, the International Neuropsychological Society, the Icahn School of Medicine at Mount Sinai, and Quebec Consortium for Drug Discovery (CQDM) Canada, all outside of the submitted work. T.K.K. has received blood biomarker data on defined research cohorts from Janssen and Alamar Biosciences for independent analysis and publication, with no financial incentive and/or research funding included. T.K.K. is an inventor on patents and provisional patents regarding biofluid biomarker methods, targets and reagents/compositions, and stands to benefit should his employer(s) transfer and/or licensing any of these resources to other organizations. K.I.E. is on the scientific advisory board for MedRhythms, Inc. and NeoAuvra, Inc. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Interaction between NfL and PWV on episodic and working memory, controlling for age, sex, site, education, and waist circumference.
See this image and copyright information in PMC

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