Plasma Amyloid Beta, Total-Tau and Neurofilament Light Chain Levels and the Risk of Stroke: A Prospective Population-Based Study

Background and ObjectivesTo unravel whether Alzheimer’s disease-related pathology or neurodegeneration play a role in stroke etiology, we determined the effect of plasma levels amyloid β (Aβ), total-tau and neurofilament light chain (NfL) on risk of stroke and its subtypes.MethodsBetween 2002 and 2005, we measured plasma Aβ40, Aβ42, total-tau, and NfL in 4,661 stroke-free participants from the population-based Rotterdam Study. We used Cox proportional-hazards models to determine the association between these markers with incident stroke for the entire cohort, per stroke subtype, and by median age, sex, Apolipoprotein E (APOE) ε4 carriership, and education.ResultsAfter a mean follow-up of 10.8 ± 3.3 years, 379 participants suffered a first-ever stroke. Log2 total-tau at baseline showed a non-linear association with risk of any stroke and ischemic stroke: compared to the first (lowest) quartile the adjusted hazard ratio for the highest quartile total-tau was 1.68, 95% CI: 1.18–2.40 for any stroke. Log2 NfL was associated with an increased risk of any stroke (HR per SD increase 1.27, 95% CI: 1.12–1.44), ischemic stroke, and hemorrhagic stroke (HR 1.56, 95% CI: 1.14–2.12). Log2 Aβ40, Aβ42, and Aβ42/40 ratio levels were not associated with stroke risk.Discussion Participants with higher total-tau and NfL at baseline had a higher risk of stroke and several stroke subtypes. These findings support the role of markers of neurodegeneration in the etiology of stroke.Classification of Evidence:This study provides Class II evidence that higher plasma levels of total-tau and NfL are associated with an increased risk of subsequent stroke.