Decomposed arterial stiffness and NfL–cognition association in older adults: The IGNITE study

Q: What is the clinical evidence from this study?

Study design: Cross-Sectional. Population: Cognitive aging in cognitively unimpaired older adults (n=552). Intervention: High structural pulse wave velocity (S-PWV) and load-dependent pulse wave velocity (LD-PWV) interacting with plasma neurofilament light chain (NfL) vs. Low S-PWV and LD-PWV (defined by sample-specific median split). Primary outcome: Moderation of plasma NfL association with working memory by structural pulse wave velocity (NfL × high S-PWV interaction) (β = -0.269 (SE = 0.114), 95% CI -0.492, -0.045, p=0.019 (FDR q = 0.067)).

Q: What does this research mean for the field?

Decomposing carotid-femoral pulse wave velocity into structural and load-dependent components does not provide multiplicity-adjusted evidence that a specific arterial stiffness component moderates the association between neurofilament light chain and cognition in older adults. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Amani M. Norling; Audrey M. Collins; Kelsey R. Sewell; Lu Wan; George Grove; Haiqing Huang; Timothy M. Hughes; Adam D. Gepner; Akira M Sekikawa; Lauren E. Oberlin; Thomas K. Karikari; Jill K. Morris; John M. Jakicic; Renee J. Rogers; Daniel E. Forman; Edward McAuley; Arthur F. Kramer; Charles H. Hillman; Eric D. Vidoni; Sandra A. Billinger; Jeffrey Murray Burns; Anna L. Marsland; Chaeryon Kang; Kirk I. Erickson

doi:10.1002/dad2.70507

Key result

Higher structural aortic stiffness shows no robust link with neurofilament light-related cognitive decline.

β = -0.269 (SE = 0.114)
95% CI -0.492, -0.045
P=0.019 (FDR q = 0.067)
n=552

Figures

Why the study?

Higher carotid-femoral pulse wave velocity strengthens associations between neurofilament light chain and poorer cognition, but whether this interaction is driven by pressure-standardized structural stiffness or transient hemodynamic load-dependent pulse wave velocity was unknown.

Does pressure-standardized structural arterial stiffness (S-PWV) or load-dependent arterial stiffness (LD-PWV) moderate the association between plasma neurofilament light chain (NfL) and domain-specific cognitive performance in cognitively unimpaired older adults?

Key Points

To determine whether the moderating effect of carotid-femoral pulse wave velocity on the association between neurofilament light chain and cognition is driven by structural or hemodynamic load-dependent arterial stiffness.
Cross-sectional baseline analysis of N=552 cognitively unimpaired older adults (aged 69.8 ± 3.8 years, 70% female) enrolled in the IGNITE study (NCT02875301).
Carotid-femoral pulse wave velocity (cfPWV) was decomposed into pressure-standardized structural stiffness (S-PWV) and transient load-dependent stiffness (LD-PWV), alongside plasma neurofilament light chain (NfL) and five latent cognitive domains.
Linear regression evaluated arterial stiffness measures as moderators of NfL–cognition links, with multiplicity controlled using Benjamini-Hochberg false discovery rate (FDR) corrections.
Plasma NfL correlated negatively with all five cognitive domains (r = -0.116 to -0.185, P < 0.01) but was not directly correlated with S-PWV (r = 0.01, P = 0.787) or LD-PWV (r = -0.01, P = 0.780).
Total-PWV nominally moderated the NfL–working memory link (β = -0.268, SE = 0.114, P = 0.019), and NfL × S-PWV interactions were nominally significant for episodic memory (β = -0.270, P = 0.040), working memory (β = -0.269, P = 0.019), and processing speed (β = -0.295, P = 0.027).
NfL × LD-PWV interactions were non-significant across all cognitive domains (P > 0.09), and none of the nominal S-PWV interactions survived FDR correction (q ≈ 0.067).

Study Design

Type

Cross-Sectional (n=552)

Multicenter

Yes

Structured PICO

Does pressure-standardized structural arterial stiffness (S-PWV) or load-dependent arterial stiffness (LD-PWV) moderate the association between plasma neurofilament light chain (NfL) and domain-specific cognitive performance in cognitively unimpaired older adults?

P

Population

552 cognitively unimpaired older adults (mean age 69.8 years, 70% female) from the multisite IGNITE baseline cohort with valid carotid-femoral pulse wave velocity and plasma neurofilament light chain measurements.

E

Exposure

Assessment and decomposition of carotid-femoral pulse wave velocity (cfPWV, measured via SphygmoCor XCEL) into model-derived pressure-standardized structural stiffness (S-PWV) and transient hemodynamic load-dependent pulse wave velocity (LD-PWV), along with plasma neurofilament light chain (NfL) measurement.

C

Comparator

Lower vs. higher PWV component groups defined by sample-specific median splits (and continuous PWV metrics).

O

Outcome

Moderation of the cross-sectional association between plasma NfL and five latent cognitive domains (episodic memory, processing speed, working memory, visuospatial processing, and executive function/attentional control) by decomposed PWV components (Total-PWV, S-PWV, LD-PWV) at baseline.surrogate

Main Result

Effect estimate: β = -0.269 (SE = 0.114) (95% CI -0.492, -0.045)

Absolute Event Rate: -0.26% vs 0.085%

p-value: p=0.019 (FDR q = 0.067)

In cognitively unimpaired older adults, pressure-standardized structural arterial stiffness (S-PWV) showed more consistent nominal moderation of the inverse association between plasma NfL and cognition than load-dependent stiffness (LD-PWV), though findings did not survive multiple testing correction.

Limitations

Cross-sectional design precludes causal inference and temporal ordering among arterial stiffness, neuroaxonal injury, and cognition
Nominal interaction findings did not survive false discovery rate (FDR) correction for multiple comparisons, and continuous interaction models were non-significant
Exclusions for missing data or low cfPWV values (<5.5 m/s) yielded a higher-functioning analytic subset, potentially limiting generalizability
Residual confounding is possible due to incomplete characterization of hypertension burden, cardiometabolic factors, and medications
PWV decomposition assumes a constant blood density because participant-specific blood density, hematocrit, and hemoglobin values were unavailable
Concomitant brain imaging markers of cerebral small vessel disease were not included
Cross-sectional design precludes defining temporal relationships among arterial stiffening, NfL, and cognitive decline
PWV × NfL interaction findings did not survive false discovery rate (FDR) correction for multiple comparisons and continuous interaction models were non-significant
Sample was predominantly women (70-71%), limiting sex-specific moderation analyses
Could not independently verify the original path-length entries for all unusually low cfPWV values (< 5.5 m/s)
S-PWV and LD-PWV are complementary model-derived components rather than direct biological measurements

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Implication

Nominal S-PWV moderation of NfL-cognition links did not survive correction; leaves open component-specific arterial stiffness effects in older adults.

Abstract

BACKGROUND: Neurofilament light chain (NfL) indexes neuroaxonal injury and relates to poorer cognition. Higher carotid-femoral pulse wave velocity (cfPWV) arterial stiffness strengthens NfL-cognition associations, but reflects both pressure-standardized structural stiffness (S-PWV) and transient hemodynamic load-dependent pulse wave velocity (LD-PWV). We tested which component drives this interaction. METHODS: Plasma NfL and cfPWV were measured in 552 cognitively unimpaired older adults. cfPWV was decomposed into S-PWV and LD-PWV. Five latent cognitive domains were modeled. Linear regression tested PWV moderators of NfL-cognition associations. RESULTS: NfL correlated with all domains (r = -0.116 to -0.185; P < 0.01) and was unrelated to S-PWV or LD-PWV. Total-PWV moderated NfL-working memory (β = -0.268, P = 0.019). NfL × S-PWV interactions were significant for episodic memory, working memory, and processing speed (P < 0.040), but did not meet false discovery rate correction (q ≈ 0.067). NfL × LD-PWV interactions were non-significant (P > 0.09). DISCUSSION: Nominal interactions were more consistent for S-PWV. Findings did not provide multiplicity-adjusted evidence of component-specific moderation.ClinicalTrials.gov: NCT02875301.

Discussion

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Cite This Study

Norling et al. (2026) conducted a cross-sectional in Cognitive aging in cognitively unimpaired older adults (n=552). High structural pulse wave velocity (S-PWV) and load-dependent pulse wave velocity (LD-PWV) interacting with plasma neurofilament light chain (NfL) vs. Low S-PWV and LD-PWV (defined by sample-specific median split) was evaluated on Moderation of plasma NfL association with working memory by structural pulse wave velocity (NfL × high S-PWV interaction) (β = -0.269 (SE = 0.114), 95% CI -0.492, -0.045, p=0.019 (FDR q = 0.067)). Higher structural pulse wave velocity nominally strengthened inverse NfL-cognition associations (working memory β = -0.269, P = 0.019), but did not survive FDR correction (q = 0.067).

synapsesocial.com/papers/6af0e999de503f3774140a17 https://doi.org/10.1002/dad2.70507

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Decomposed arterial stiffness and NfL–cognition association in older adults: The IGNITE study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Decomposed arterial stiffness and NfL–cognition association in older adults: The IGNITE study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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