LAUSR

BACKGROUND AND OBJECTIVES To 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. METHODS Between 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. RESULTS After 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.