Plasma Neurofilament Light Chain and Incident Cardiovascular Outcomes in the General Population

ImportanceStandard cardiovascular risk scores fail to predict a substantial fraction of incident vascular clinical events in the general population. Whether circulating neurofilament light chain (NfL), a blood-based biomarker of neuronal axonal injury, independently predicts major cardiovascular or cerebrovascular disease outcomes in adults without known baseline clinical disease has not been tested. ObjectiveTo determine whether plasma NfL is independently associated with incident cardiac and brain vascular events in community-recruited adults and whether it adds prognostic information beyond established clinical risk factors. Design, Setting, and ParticipantsProspective cohort analysis within the UK Biobank. Plasma NfL was quantified using the Olink Explore proximity extension assay in 50,043 adults aged 40-69 years at recruitment. After excluding 3,914 participants with baseline known disease, the primary analysis included 46,129 adults. Incident events were ascertained via registry linkage over a median follow-up of 9.6 years. ExposuresPlasma NfL, quantified in Olink Normalized Protein eXpression (NPX) units. Main Outcomes and MeasuresPrimary outcome: major cardiovascular event (MVE), defined as the composite of cardiovascular death, nonfatal stroke, and nonfatal MI. Secondary outcomes: individual MVE components, heart failure hospitalization, and all-cause mortality. ResultsAmong 46,129 participants free of baseline disease diagnoses, there were 2,912 incident MVE events. After adjustment for age, sex, BMI, smoking, hypertension, diabetes, and renal function, each one-NPX-unit increase in NfL was independently associated with MVE (aHR 1.46 (95% CI 1.36-1.57; P < .001)), nonfatal stroke (aHR 1.38 (95% CI 1.22-1.57; P < .001)), MI (aHR 1.35 (95% CI 1.22-1.50; P < .001)), cardiovascular death (aHR 1.79 (95% CI 1.59-2.01; P < .001)), heart failure hospitalization (aHR 1.50 (95% CI 1.36-1.65; P < .001)), and all-cause mortality (aHR 1.21 (95% CI 1.18-1.25; P < .001)). The associations were log-linear with no evidence of a threshold or saturation effect. Results were consistent in a sensitivity analysis including the full cohort with baseline vascular disease diagnoses. Addition of NfL to traditional risk factors improved 10-year discrimination most for cardiovascular death (C-statistic 0.809 to 0.817; {Delta}C = 0.007), heart failure ({Delta}C = 0.006), and stroke ({Delta}C = 0.008), with a smaller increment for the MVE composite. Conclusions and RelevancePlasma NfL was independently associated with incident cardiovascular and cerebrovascular outcomes among community-recruited adults after comprehensive risk-factor adjustments. These findings suggest that blood NfL levels may serve as a biomarker of subclinical vascular disease, strengthening early detection efforts and prompting further diagnostic evaluation.