BMI and Allostatic Load Are Directly Associated with Longitudinal Increase in Plasma Neurofilament Light among Urban Middle-Aged Adults

Background Plasma neurofilament light chain (NfL) is a novel biomarker for age-related neurodegenerative disease. We tested whether NfL may be linked to cardiometabolic risk factors, including BMI, the allostatic load (AL) total score (AL(total)), and related AL continuous components (AL(comp)). We also tested whether these relations may differ by sex or by race. Methods We used data from the HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span) study [n = 608, age at visit 1 (v(1): 2004-2009): 30-66 y, 42% male, 58% African American] to investigate associations of initial cardiometabolic risk factors and time-dependent plasma NfL concentrations over 3 visits (2004-2017; mean +/- SD follow-up time: 7.72 +/- 1.28 y), with outcomes being NfL(v1) and annualized change in NfL (delta NfL). We used mixed-effects linear regression and structural equations modeling (SM). Results BMI was associated with lower initial (gamma(01) = -0.014 +/- 0.002, P < 0.001) but faster increase in plasma NfL over time (gamma(11) = +0.0012 +/- 0.0003, P < 0.001), a pattern replicated for AL(total). High-sensitivity C-reactive protein (hsCRP), serum total cholesterol, and resting heart rate at v(1) were linked with faster plasma NfL increase over time, overall, while being uncorrelated with NfL(v1) (e.g., hsCRP x Time, full model: gamma(11) = +0.004 +/- 0.002, P = 0.015). In SM analyses, BMI's association with delta NfL was significantly mediated through AL(total) among women [total effect (TE) = +0.0014 +/- 0.00038, P < 0.001; indirect effect = +0.00042 +/- 0.00019, P = 0.025; mediation proportion = 30%], with only a direct effect (DE) detected among African American adults (TE = +0.0011 +/- 0.0004, P = 0.015; DE = +0.0010 +/- 0.00048, P = 0.034). The positive associations between AL(total)/BMI and delta NfL were mediated through increased glycated hemoglobin (HbA1c) concentrations, overall. Conclusions Cardiometabolic risk factors, particularly elevated HbA1c, should be screened and targeted for neurodegenerative disease, pending comparable longitudinal studies. Other studies examining the clinical utility of plasma NfL as a neurodegeneration marker should account for confounding effects of BMI and AL.

Automated summary

This study found associations between plasma neurofilament light chain (NfL) concentrations and cardiometabolic risk factors such as BMI and allostatic load, with potential differences by sex or race. Factors like BMI, high-sensitivity C-reactive protein (hsCRP), and serum total cholesterol were linked to faster increase in NfL concentrations over time, possibly mediated by glycated hemoglobin concentrations.