To unravel whether Alzheimer disease-related pathology or neurodegeneration plays a role in stroke etiology, we determined the effect of plasma levels β-amyloid (Aβ), total-tau, and neurofilament light chain (NfL) on risk of stroke and its subtypes.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, APOE ε4 carriership, and education.After a mean follow-up of 10.8 ± 3.3 years, 379 participants had a first-ever stroke. Log2 total-tau at baseline showed a nonlinear association with risk of any stroke and ischemic stroke: compared to the first (lowest) quartile, the adjusted hazard ratio (HR) 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 1-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.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.This study provides Class II evidence that higher plasma levels of total-tau and NfL are associated with an increased risk of subsequent stroke.